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Cancer-associated fibroblasts and their influence on tumor immunity and immunotherapy

Richard Lee Barrett, Ellen Puré

eLife · 2020 · Review · CC BY

doi:10.7554/elife.57243 (opens in a new tab)

Abstract

Fibroblasts play an essential role in organogenesis and the integrity of tissue architecture and function. Growth in most solid tumors is dependent upon remodeling ‘stroma’, composed of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM), which plays a critical role in tumor initiation, progression, metastasis, and therapeutic resistance. Recent studies have clearly established that the potent immunosuppressive activity of stroma is a major mechanism by which stroma can promote tumor progression and confer resistance to immune-based therapies. Herein, we review recent advances in identifying the stroma-dependent mechanisms that regulate cancer-associated inflammation and antitumor immunity, in particular, the interactions between fibroblasts and immune cells. We also review the potential mechanisms by which stroma can confer resistance to immune-based therapies for solid tumors and current advancements in stroma-targeted therapies.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Cancer cells must construct an extensive network of local and distant communications in order to establish a ‘neo-organ’ system that provides the connective tissue cells, extracellular matrix (ECM), vasculature, and immune privilege required to sustain tumor growth. While traditionally, therapies were designed to target the cancer cells directly, recent complementary efforts are aimed at disrupting such networks that support malignant cell behavior and are proving to be a successful therapeutic space. Examples include anti-angiogenic drugs and immunotherapies that are rapidly changing the therapeutic landscape for a wide variety of cancers. Moreover, cancer-associated fibroblasts (CAFs) are emerging as potential therapeutic targets in the rapidly expanding field of stroma-targeted therapies designed to complement malignant cell-targeted therapies.

Immunotherapies are proving particularly effective in the clinic and are rapidly being incorporated into standards of care, alongside chemotherapy, for a variety of cancer types. Immunotherapy can be broken down into two general categories. The first are therapies designed to activate or amplify the immune system through small molecules, biologics, or antibodies. Such therapies include cancer vaccines, immune agonists such as anti-CD40, and inhibitors of immune checkpoints such as anti-CTLA-4 and anti-PD-1/PD-L1 antibodies. The second is based on adaptive transfer of immune cells such as T cells expressing tumor antigen reactive T cell receptors (TCR) and chimeric antigen receptor (CAR) expressing T cells (CAR-T). However, while effective in some patients, substantial proportions of patients are resistant to or acquire resistance to immune modulators. Moreover, although CAR-T cell therapy has been particularly effective in hematologic tumors, little success has been realized to date in solid tumors with this approach. Such resistance highlights the need for better understanding of how tumor immunity is regulated in the tumor microenvironment (TME).

Although their functionality has been largely overlooked in the context of cancer, fibroblasts—and their associated matrix—account for the majority of tumor mass in many cancer types and fibroblasts are known to influence malignant cells behavior through both biochemical and biomechanical signals. Additionally, fibroblasts can exert a strong immunomodulatory influence, regulating the infiltration and phenotype of immune cells within the TME and influencing their spatial localization and functionality intra-tumorally. In this review, we focus on the intersection of fibroblast-derived factors and tumor immunity and discuss the role of fibroblasts in immunotherapy resistance.

Fibroblast activation

Fibroblasts are a difficult cell type to define due to a lack of unique markers expressed exclusively and by all fibroblasts. Fibroblasts are heterogeneous populations of mesenchymal cells that perform essential roles in formation and maintenance of connective tissue ECM and govern parenchymal cell behavior. Fibroblasts are found in virtually all tissues and, under homeostatic conditions, exist in a quiescent state defined by a low proliferative capacity and metabolic state. Fibroblasts, like resident leukocytes, serve as sentinels that sense disruptions in homeostasis, and fibroblast activation is a common early response to such disruptions. Activation is characterized by increased proliferative capacity, increased synthetic activity—including production of a provisional matrix and production of growth factors, cytokines, and chemokines—and increased metabolic activity, all designed to restore homeostasis. This reparative fibro-proliferative response is arguably best understood in the context of wound healing, where specialized subsets of activated fibroblasts proliferate and migrate into the wound site, produce ECM to restore damaged tissue, and act in concert with inflammatory, immune, and other cells as necessary to restore homeostasis. However, many features of fibroblast activation are shared in other contexts, including cancer, where activated CAFs can strongly influence the TME. Moreover, both quiescent and activated fibroblasts are heterogeneous and exhibit marked context-dependent diversity in their phenotypes and functionality.

Understanding the relationship between tumor cells, tumor infiltrating immune cells, and CAFs has been hampered by an incomplete understanding of CAF biology such as the intrinsic and extrinsic factors involved in their activation. The mechanisms underlying the phenotypic and functional heterogeneity, spatiotemporally dynamic evolution, and plasticity of CAFs are also poorly understood. Cancer cells can drive fibroblast activation through both biochemical and biomechanical mechanisms (Figure 1). Tumor cell secreted factors (for example, TGF-β, PDGF, EGF, CTGF, and FGF), and tumor cell-derived exosomes, have been implicated in fibroblast activation. As with classical wound healing, CAFs can also become activated in response to damage-associated molecular patterns (DAMPs) released by damaged tissue or necrotic tumor cells. These signals are sensed by fibroblasts through pathways such as the NLRP3 inflammasome.

In addition to malignant cells, endothelial, inflammatory and immune cells in the TME also secrete mediators of fibroblast activation. Moreover, activated fibroblasts produce factors and matrix that drive their autocrine activation in a feed-forward manner, as fibroblasts are responsive to substratum composition and stiffness. Stiffness within compliant normal tissues typically ranges from ~0.05 to 5kPa, while progressive stiffening of tumor tissue can reach up to ~20 kPa in the most desmoplastic tumors such as pancreatic cancer. Moreover, substratum composition and stiffness may also be important factors in driving heterogeneity amongst activated fibroblasts. Integration of biochemical and biomechanical signals can also drive dedifferentiation of other mesenchymal cell types, such as pericytes and adipocytes, to a CAF-like state. Notably, diverse cancer types and tumors at different stages of progression, can vary with regard to prevalence of, and dependence on stroma.

Activated fibroblasts are heterogeneous

In view of clinical evidence for a correlation between CAF markers and poor overall prognosis in multiple cancer types, CAFs were conventionally considered to be pro-tumorigenic. However, initial attempts at depleting myofibroblasts from the TME unexpectedly enhanced tumor progression. Such seemingly confounding observations led to the current push to better understand the heterogeneity of fibroblasts within the TME.

Historically, it was common to rely on expression of alpha-smooth muscle actin (α-SMA) as a hallmark of activated fibroblasts. These fibroblasts were generically referred to as ‘myofibroblasts’. Myofibroblasts were originally defined in the context of wound healing where their expression of components of the contractile apparatus typical of smooth muscle cells—including α-SMA—confers cells with the contractile function critical for wound closure and contribute to tissue tension. Myofibroblasts are indeed common to multiple physiologic reparative responses and also to pathologic conditions such as scarring, tissue fibrosis, and to solid tumors that are characterized by a sustained pathogenic fibro-proliferative response. However, myofibroblasts represent only a subset of activated fibroblasts within the TME.

CAFs are in fact heterogeneous based on phenotypic markers, gene expression profiling, and functionality. So far, a pan-specific CAF marker has yet to be identified and neither a unifying approach to defining, nor a standardized nomenclature for CAF subpopulations has yet emerged. Defining CAF subsets promises to be complex based on evidence that the state of fibroblast activation is both context-dependent and plastic.

Further adding to the complexity is that fibroblasts in healthy tissue, from skin to pancreas, exhibit heterogeneity even before activation. Understanding this underlying heterogeneity is vital to understanding the development of CAFs within the TME. For example, two mostly distinct populations comprise the local fibroblasts in healthy pancreas—identified as Gli1+ and Hoxb6+, respectively—however, lineage-tracing studies demonstrated that these two populations do not contribute equally to CAF development in pancreatic cancer. Specifically, the Gli1+ population was found to expand significantly during carcinoma development, while the more stellate cell-like Hoxb6+ fibroblasts did not appear to contribute to the same degree. Additional lineage-tracing experiments will provide critical insights and facilitate future understanding into how resident fibroblast populations might differentially contribute to CAF development.

In established tumors, recent single-cell sequencing analyses indicate that fibroblasts segregate into anywhere from three to seven major clusters based on transcriptome. However, it is premature to make conclusions regarding the extent to which multiple subpopulations—being defined by gene signatures based on single cell RNAseq data—may overlap between diverse fibroinflammatory settings or even between CAFs described in different types of carcinomas. Current evidence taken together does however suggest that there is considerable context-dependent variability in definable CAF clusters between tumor types and also between TME and other fibroinflammatory conditions. Further analysis across tumor types and other fibroinflammatory settings will be required to reveal any potentially unifying patterns of subpopulations of activated fibroblasts in diverse pathophysiologic settings. Nonetheless, some patterns are emerging within particular tumor types, and there is now some evidence for shared subpopulations of CAFs defined by phenotype or gene expression signatures between tumor types as discussed below.

Two broadly defined subpopulations referred to as myCAFs and iCAFs, were first described in pancreatic cancer. Single-cell analysis of stroma provided evidence of similar populations in other cancer types, such as lung and colorectal cancer (CRC).

MyCAF encompass the traditional myofibroblast population mentioned earlier. MyCAFs tend to be enriched amongst the most tumor adjacent fibroblasts where tumor secreted factors such as TGF-β, and microenvironmental cues such as increased tissue stiffness, drive and sustain the phenotype. MyCAFs are hyperproliferative compared to other CAF populations and in certain contexts may be tumor restraining. iCAF refers to an inflammatory CAF phenotype, defined by expression of cytokines such as IL-6 and CXCL12, and commonly identified by expression of Ly6C. Ly6C is also a marker of inflammatory macrophages raising the interesting possibility of a common transcriptional program regulating inflammatory genes shared by multiple cell types that contribute to the inflammatory milieu in the TME. The iCAF population tends to be more distal from the edge of tumor cell nests and is driven by tumor secreted factors such as IL-1(46, 47). IL-1 signaling can drive expression of autocrine signals in iCAFs such as LIF, which help to maintain their inflammatory phenotype. These two populations are interconvertible with evidence suggesting that myCAFs may dominate functionally in at least some instances where both populations are present. Studies highlighting these two populations in pancreatic cancer have also described a third population defined by their expression of MHC-II and thus described as antigen-presenting CAFs (apCAFs). The variable influence of these different CAF populations on tumor immunity is further discussed throughout this review.

Determining whether iCAF and myCAF designations based on these criteria will apply broadly awaits single-cell RNA sequencing of additional tumor types and validation at the protein and functional levels. Further studies will also be required to relate these designations to other phenotypically and functionally defined subpopulations.

Independently, a number of other markers defining activated fibroblast subpopulations have been noted. These include CD29, CD90, caveolin (CAV1), fibroblast activation protein (FAP), podoplanin (PDPN), fibroblast-specific protein 1 (FSP-1/S100A4), meflin, and platelet-derived growth factor receptor alpha (PDGFRα) (;;; Table 1). These markers can be used alone or combinatorically to distinguish subpopulations with key functional differences within the TME (see Table). For example, FAP expressing fibroblasts can be further divided based on functionality and/or the presence of other markers such as α-SMA, while PDPN+ cells can be subdivided by their expression of FAP, with the FAP-PDPN+ cells being identified as pericytes for instance (Table 1; ).

CAF-immune cell interactions

CAFs are now understood to be a major source of immunosuppressive activity in the TME (Figure 1). Fibroblasts can influence immune cell infiltration either directly—via secreted cytokines and chemokines and cell surface proteins—or indirectly—through deposition of various ECM components and remodeling of matrix on which immune cells depend for intra-tumoral localization and migration. Better defining these interactions is particularly important in the context of expanding immunotherapies, as CAFs can not only influence de novo immune responses but dictate the success of immunotherapies as well. Notably, many studies of CAF-immune cell interactions to-date were performed using heterogeneous CAF populations and therefore, specific observations may be manifestations of either a balance between multiple subpopulations or of a predominant subpopulation present. Importantly, the representation of distinct subpopulations may vary dramatically depending on in vivo context.

Although remodeling of ECM by tumor cells, inflammatory cells, and CAFs is another important mechanism by which immune cell recruitment and function are regulated in the TME, in the interest of space and focus, in this review, we focus our discussion in particular on direct signaling between CAFs and immune cells in the context of cancer and refer the reader to other recent reviews that focus on ECM influences on tumor immunity.

Myeloid cells

Myeloid cells are well studied in the context of the TME where they exhibit remarkable phenotypic plasticity, but often acquire an immunosuppressive state that suppresses cytotoxic T cell activity and subdue anti-tumor immunity. Early evidence that CAFs may contribute to this immunosuppressive phenotype was based on clinical data showing a correlation between stromal markers and immunosuppressive cell types such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSC). The development of MDSCs correlates not only with poorer overall survival across a variety of cancers, but also with whether or not patients will respond to immunotherapy.

CAFs can secrete a number of factors known to influence both recruitment and activation state of myeloid cells including: Chi3L1, CXCL1, CXCL2, CXCL5, CXCL6/GCP-2, CXCL8, CXCL9, CXCL10, CXCL16, CXCL12/SDF1, CCL2/MCP-1, CCL3, CCL5/Rantes, CCL7, CCL20, CCL26, IL-1β, IL-6, IL-8, IL-10, leukemia inhibitory factor (LIF), VEGF, TGF-β, indoleamine-2,3-dioxygenase (IDO), prostaglandin (PG) E2 (PGE2), tumor necrosis factor (TNF), or nitric oxide (NO). To date, only a handful have been directly implicated in CAF-immune crosstalk within the TME (Figure 1).

Two of the more well-studied pathways in CAF-myeloid interactions are CXCL12/CXCR4 and IL-6/STAT3. CAFs are the primary source of CXCL12 in the TME. CXCL12 recruits myeloid cells to the TME while inducing an immunosuppressive phenotype. Inhibiting either CXCL12 or its receptor CXCR4 is sufficient to decrease intra-tumoral MDSCs and improve overall immune response to a variety of cancers. Expression of CXCL12/CXCR4 is regulated by PGE2 and TGF-β and these have been proposed as potential upstream targets for inhibiting this signaling axis.

The IL-6/STAT3 pathway has a similar effect. CAF-derived IL-6 drives STAT3 activation in myeloid cells, driving them to more immunosuppressive cell types such as regulatory dendritic cells (DCs). Blocking either CAF IL-6 or myeloid STAT3 can disrupt signaling from CAFs to myeloid cells and attenuate immunosuppression in hepatocellular carcinoma (HCC) and pancreatic cancer.

Also within the IL-6 family of cytokines, LIF and IL-11 have been identified as major mediators of CAF paracrine signaling and STAT3 activation in the TME. LIF signaling from CAFs drives immunosuppressive gene expression in TAMs that includes upregulation of CCL2—an important signal for myeloid cell attraction to the TME—and silencing of CXCL9—a cytokine which drives recruitment of cytotoxic T-cells. While CAFs can elicit CCL2 expression from TAMs via this LIF-mediated paracrine signaling, CAFs—in particular FAP+ CAFs—are capable of producing CCL2 directly. These FAP+ CAFs are also known to be the main source of CXCL12 in the TME. Such expression patterns bring up an important concept in regard to CAF heterogeneity that, while many CAF signaling pathways are often described at a whole population level, many specific cytokines can be traced back to specific CAF subpopulations.

Other myeloid targeting cytokines produced by CAFs include CXCL16 and IL-33—both important for myeloid cell recruitment, chitinase 3-like 1 (Chi3L1)—which drives M2 polarization in macrophages, and CXCL1—which has been implicated in CAF-mediated myeloid suppressor cell accumulation with important considerations in therapy as discussed below. However, which CAF signaling pathways are the predominant drivers of myeloid phenotype are context-dependent as, studies showing the role of IL-8/CXCR2 in the recruitment of myeloid cells in CRC were associated with little, if any, contribution from CXCL12/CXCR4. The ratio of different fibroblast subpopulations and influence of the specific cancer type likely play a role in determining the dominate signaling pathways.

T cells

Given that T cells are prominent cytotoxic responders to cancer cells, some of the most extensive work on CAFs’ role in tumor immunity have been done in this space. Understanding these interactions is of compounded importance as many of the barriers to efficacy in T-cell-based therapies, such as checkpoint blockade and adoptive T cell therapy like CAR-T, are thought to be a result of these immunosuppressive stromal interactions.

As with myeloid cells, CAF markers reportedly correlate with immunosuppression of T cells in the TME, as defined by an increased ratio of FoxP3+ T cells over CD8+ T cells, which was also associated with poor clinical outcome. While this regulation of the adaptive immune response could be explained by CAFs’ effects on myeloid cells, CAFs can also act on T cells directly by promoting regulatory T cells and blocking the effects of cytotoxic T cells (; Figure 1).

The role of CAFs in driving regulatory T cell responses is supported by experiments showing that flank tumors co-injected with fibroblasts show a greater ratio of FoxP3+ to CD8+ T cells than tumor cells injected alone. This effect is thought to be mediated via CAF secreted IL-6 as, anti-IL-6 antibodies attenuated the immune effect in vivo. Further, fibroblast IL-6 drives differentiation of other regulatory T cells such as interleukin-17 (IL-17)-producing T helper (TH17) cells. TH17 cells exhibit both pro- and anti-tumorigenic effects depending on the tumor type. On one side, TH17 cells can recruit CD8+ T cells to the TME helping to drive antitumor immune response; on the other, IL-17 released from TH17 cells can in turn, drive production of angiogenic factors from fibroblasts and cancer cells, thus fueling tumor growth. The role of TH17 cells varies between cancer types and is likely determined by the TME and further signaling from CAFs.

T cells also interact with a number of cell surface ligands displayed by CAFs including B7H3, CD73, DPP4, JAM2, and OX40L (; Figure 1). CAF expression of JAM2, OX40L, and PD-L2, significantly increases the duration of contact time between T cells and CAFs, while B7H3, CD73, and DPP4 play a more direct role in allowing CAFs to drive expansion of CD25+FOXP3+ T cell numbers. B7H3 is an immune checkpoint molecule, CD73 converts AMP to immunosuppressive adenosine, and DPP4 cleaves the proinflammatory cytokine CXCL10 to a truncated version that acts as an antagonist to its own receptor CXCR3(101). All three targets are expressed by cells other than fibroblasts within the TME, including cancer cells themselves, so the extent to which CAF-specific expression influences the TME may vary. Still, potential immunotherapies are developing around each target with success in early preclinical models.

CAFs can also influence T cell immunity through antigen presentation. CAFs are capable of sampling, processing, and presenting tumor antigens via major histocompatibility complex 1 (MHC-I). T cells engage the MHC-I-antigen bimolecular complex along with PD-L2 and FASL on the CAF cell surface. The combined signaling can result in killing of antigen-specific cytotoxic CD8 T cells. In addition to MHC-I-dependent antigen presentation, a population of MHC-II expressing fibroblasts, mentioned earlier in the review as apCAFs, have also been described in pancreatic cancer. However, unlike professional antigen presenting cells, apCAFs express PGE2 and lack co-stimulatory ligands necessary to activate immune cells so that MHC-II signaling apCAFs promotes expansion of CD4+, CD25high, Foxp3+ regulatory T cells (Tregs) rather than activation of effector T cells with potential to mediate antitumor immunity. It should be noted that detection of apCAFs is variable, even within the pancreatic TME in which they have been described.

PD-L1 and PD-L2 are important signaling ligands expressed by many cell types to limit T cell function and prevent autoimmunity. Consequently, PD-L1/2 expression in the TME promotes immunosuppression, protecting cancer cells from T cell-mediated killing, and thus has become an important target for checkpoint inhibition. Fibroblasts within the TME can express PD-L1/2 themselves as well as increase PD-L1/2 expression in tumor cells via CXCL5 signaling—as shown in melanoma and CRC—or miR-92 delivered via CAF-derived exosomes—as shown in breast cancer.

Even when T cells are functionally capable of mounting a response against tumor cells, as would be the case in the presence of checkpoint inhibitors or in the case of adoptively transferred CAR-T cells, the stroma consisting of CAFs and remodeled ECM, can act as a formidable barrier to T cells, resulting in T cell exclusion from tumor nests. Expression of TGF-β-associated ECM genes in CAFs is one of the strongest predictors of immunotherapeutic failure, and co-administration of anti-TGF-β antibodies and anti-PD-L1 antibodies significantly improved success of immunotherapy in preclinical models. Inhibiting TGF-β renders solid tumors more T cell responsive and susceptible to therapies such as anti-PD-1-PD-L1 therapy. Specific downstream targets of TGF-β that contribute to this effect include NOX4, and inhibition of NOX4 makes tumors more susceptible to immunotherapy. The CXCL12/CXCR4 pathway also drives T cell exclusion and inhibition of CXCL12 with the clinical-stage l-RNA-aptamer NOX-A12 also improved response to anti-PD-1 therapy.

Not all fibroblast-mediated signaling in the TME is immunosuppressive however, and a number of studies highlight fibroblast populations capable of stimulating cytotoxic T cell responses. In some settings, IL-6 signaling from fibroblasts exposed to T cells enhanced T cell stimulation. Such data highlights the functional and clinical significance of CAF heterogeneity in vivo with certain populations performing opposing functions and exhibiting distinct secretomes. It is worth noting, that immune suppressive fibroblast populations may even be over-represented in past literature, as common in vitro methods of cultivating fibroblasts can promote transition of fibroblasts into an immunosuppressive state, artificially minimizing the potential contribution of other populations.

Natural killer cells

Our understanding of the role of natural killer (NK) cells in tumor immunity has grown considerably in recent years. Like T cells, NK cells possess the intrinsic ability to detect and kill malignant cells. However, also similar to T cells, NK cell responses are greatly influenced by CAFs in the TME which can interfere with NK cell-mediated killing.

In co-culture, CAFs interfere with key processes in NK cell activation including IL-2-mediated up-regulation of triggering receptors NKp44, NKp30, and DNAM-1 and acquisition of cytolytic granules. While DNAM-1 inhibition appears to be contact-dependent with CAFs, inhibition of NKp44 and NKp30 expression is driven by CAF secretion of PGE2(122). Also contact-dependent, expression of podoplanin in certain fibroblast subpopulations can interfere with CCL21/CCR7-directed adhesion and migration of NK cells in the TME (; Figure 1).

PGE2 is a major CAF-derived inhibitor of NK cell function in both CRC and HCC, and inhibitors of either PGE2, or its downstream target indoleamine 2,3-dioxygenase (IDO) ablate the effect in culture. However, PGE2 does not appear to be a primary regulator in all cancer types, as CAFs derived from endometrial cancer are able to promote NK dysfunction independent of PGE2 signaling, and instead do so by downregulating cell surface poliovirus receptor (PVR/CD155), an important DNAM-1 ligand that is normally present on endometrial fibroblasts.

CAF signaling can also act upon tumor cells to render them more resistant to NK-mediated killing. CAF-secreted matrix metalloproteinases (MMPs) decrease expression of MHC class I chain-related protein A and B (MICA/B) in tumor cells, which are important ligands for NK cells in recognizing distressed or malignant cells. Broad MMP inhibitors are able to ablate this effect.

As NK cells become a major focus as candidates for novel off-the-shelf adoptive cell immunotherapies, they are likely to face many of the same barriers within the TME as T cells. Better understanding of the relationship between CAFs and NK cells will be vital going forward in order to give such therapies the best chance at therapeutic success.

Mast cells

Mast cells can have varying effects on the TME. On one hand, mast cells drive a number of pro-tumorigenic processes in the TME, such as immunosuppression via expression of PD-L1 and promoting angiogenesis. On the other, mast cell infiltration into the TME is correlated with a positive prognosis across multiple cancers.

CAFs are able to recruit mast cells to the TME via CXCL12/CXCR4 signaling (Figure 1) in prostate cancer but infiltrating mast cells were shown to be pro-tumorigenic in this setting. Once recruited, mast cell signaling can enhance a variety of fibroblast functions including contraction of collagen lattices via stem cell factor (SCF)/c-kit signaling and increased production of collagenolytic enzymes via IL-1α and TNFα signaling. The broad and often conflicting functions of mast cells within the TME is an area in need of further study but given the close interactions of mast cells and fibroblasts, it is likely CAFs may be a major determinant in the role mast cells play.

Neutrophils

As with many of the immune cell types mentioned above, neutrophils can have both antitumor and pro-tumor functions, although infiltration of tumor-associated neutrophils (TANs) correlates with negative outcome in many solid tumors. In gastric cancer, TANs drive CAF formation by producing inflammatory cytokines like IL-17, IL-23, and TNF-α. In pancreatic cancer, neutrophil extracellular traps (NETs) produced in response to pancreatic cancer metastases drive CAF formation in liver micrometastases, and treatment with DNase1 can significantly reduce CAF formation and metastasis growth in these models.

On the flip side, CAFs can significantly influence neutrophils in the TME. Studies in breast cancer show that CAFs recruit neutrophils to the TME via IL-33 and CXCL12. TANs recruited to the TME respond to CAF secreted IL-6 (Figure 1), as shown in both gastric cancer and HCC, which drives STAT3 and PD-L1 expression, allowing neutrophils to inhibit T cell function. Given that the role of neutrophils within the TME is only beginning to be understood at a mechanistic/molecular level, research directly connecting CAFs to neutrophils is still in early stages. However, neutrophils respond to many of the pathways already discussed in detail above and it is likely that they are an integral player in much of the CAF-immune crosstalk described.

CAFs and cancer therapy

With the recent successes of immunotherapy in the treatment of cancer, obstacles to efficacy in the clinic have also emerged: (1) Immunotherapies work remarkably well in a subset of patients while being ineffective in many other patients, the reasons for which are still not completely understood and (2) some immunotherapies have struggled, particularly in highly stromagenic cancers such as pancreatic cancer, where almost no immunotherapeutic success has been realized. A greater understanding of how the tumor stroma and overall TME influence these therapies will provide important advances in these areas.

It is for these reasons that CAFs are a lucrative target for novel cancer therapies. Depletion of CAFs and targeting of CAF-dependent pathways can indirectly result in the death of malignant cells through both immune-dependent mechanisms and immune-independent mechanisms. Given that ECM dysregulation is one of the strongest predictors of failure in immunotherapies such as PD-L1 blockade, combinatorial approaches targeting immune cells and CAFs have been at the forefront. Another, arguably even more compelling, concept being developed is to use stroma-targeted therapies to make tumors more vulnerable to other types of therapies, including chemo-, tumor cell-targeted, and immuno-therapies.

Several approaches are being taken to target fibroblasts: (1) targeting upstream pathways that drive fibroblast differentiation and reprogramming of CAFs, (2) taking advantage of the heterogeneity of the population in order to shift the influence of pro- versus anti-tumorigenic populations, and (3) targeting downstream effector pathways by which activated fibroblasts negatively influence the TME (Figure 2).

Targeting specific CAF subpopulations

Early attempts to therapeutically target CAFs within the TME were unsuccessful in preclinical models and in patients, and actually worsened tumor prognosis. These early attempts, however, were limited by an incomplete understanding of fibroblast heterogeneity and in retrospect may have selectively targeted populations of myofibroblast-like CAFs by specifically depleting SMA+ cells or targeting the sonic hedgehog pathway. These populations can exert tumor restraining activity in the particular cancer context studied. In contrast, targeting other populations of fibroblasts have provided promising results.

One of the most successful approaches has been in targeting FAP+ fibroblasts. FAP+ cells can both promote tumor progression directly and present a barrier to immunotherapies through their production of ECM and direct signaling pathways. They are also major producers of certain immunosuppressive cytokines such as CXCL12 and CCL2 as mentioned earlier. As a result, depleting this population is thought to be an effective way to disrupt the desmoplasia and thus enhance immune infiltration, while either leaving tumor suppressing populations of fibroblasts undisturbed, or also resulting in depletion of such populations, but with the anti-tumorigenic depletion of the FAP+ cells proving dominant.

Indeed, multiple different approaches to depleting this population have shown success, from genetic depletion, to using more translatable approaches like vaccines, drug delivering nanoparticles that are activated upon cleavage by FAP, FAP antibody-drug conjugates (ADCs), and CAR-T cells directed at FAP+ cells (;; Figure 2). Such treatments are typically designed to enhance the activity of conventional chemotherapies and immunotherapies but have also shown efficacy on their own, perhaps through favoring an immune permissive environment. So far, FAP+ populations have been the primary focus in stromal depletion therapies but as definition of CAF subpopulations are refined, we will likely see other targets taken advantage of.

Targeting upstream and downstream pathways in CAFs

Of the therapies moving into, or already in the clinical space, there are two major therapeutic approaches being explored to target CAFs for cancer therapy. The first approach involves targeting with the upstream signaling required to drive fibroblasts from tumor restraining populations to tumor permissive or promoting (Figure 2). Drugs targeting these pathways currently include FAK inhibitors, Hedgehog inhibitors, fibroblast growth factor receptor (FGFR) inhibitors, connective tissue growth factor (CTFG) antagonists, and TGF-β inhibitors. Targets such as TGF-β are multifaceted, influencing both CAF formation and downstream signaling of already established CAF populations.

The second approach involves targeting fibroblasts already transitioned to a tumor promoting/permissive state (Figure 2). These include therapies to reprogram activated CAFs to a more quiescent-like state, such as Vitamin D receptor agonists of which the drug paricalcitol has already entered phase I clinical trials. Other therapies influence CAF matrix deposition, decompressing the tumor, normalizing vasculature, and thus conferring susceptibility to chemo- and immunotherapy. Examples include the angiotensin inhibitor losartan and enzymatic therapeutics like PEGPH20, a pegylated hyaluronidase enzyme designed to degrade hyaluronic acid produced by fibroblasts in the TME. Hyaluronidase treatment showed promise in animal models and early clinical trials. However, PEGHP20 in combination with nab-paclitaxel/gemcitabine failed to meet its primary endpoint of increased overall survival in Phase III clinical trials in pancreatic cancer patients and further development of the drug was halted.

Treatments that target CAFs effector mechanisms that mediate their tumor promoting or immunosuppressive effects are also being developed. The RNA oligonucleotide drug NOX-A12 neutralizes CXCL12, inhibiting CXCR4 binding. NOX-A12 showed favorable responses in early clinical trials with pancreatic cancer and CRC and is continuing to be investigated clinically.

TGF-β is another downstream target with multiple attempts to target the pathway underway, including antisense oligonucleotides, neutralizing antibodies to TGF-β, and antibodies which block the TGF-β receptor TβRII. However, many of these therapeutic strategies target TGF-β throughout the body and across multiple cell types. This could potentially limit efficacy seeing as TGF-β can be tumor suppressive under certain conditions. More directed approaches can sidestep TGF-β’s immunosuppressive effects possibly limiting off-target effects. For example, novel CAR-T cell therapies are being designed to maintain activation in the presence of TGF-β by co-expressing a dominant-negative TGF-βRII.

It is becoming clear that fibroblasts play a major role in how immune cells respond to a variety of homeostatic perturbations and particularly cancer. Despite providing support for almost every major organ system in the human body, fibroblast biology has been overlooked in many disease processes. The recent push to understand their role in the context of tumor immunity and how their activation influences various biological systems will yield invaluable insight into how to improve cancer therapy and undoubtedly provide insight into many other disease processes as well.

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    Barreira da Silva R, Laird ME, Yatim N, Fiette L, Ingersoll MA, Albert ML. Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nature Immunology. 2015;16:850-858.

    Not in our library10.1038/ni.3201 (opens in a new tab)

  10. 10.
    Natural Killer Cells as Key Players of Tumor Progression and Angiogenesis: Old and Novel Tools to Divert Their Pro-Tumor Activities into Potent Anti-Tumor Effects · 2019
    No notice
  11. 11.

    Beatty GL, Li Y, Long KB. Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists. Expert Review of Anticancer Therapy. 2017;17:175-186.

    Not in our library10.1080/14737140.2017.1270208 (opens in a new tab)

  12. 12.

    Beavis PA, Stagg J, Darcy PK, Smyth MJ. CD73: a potent suppressor of antitumor immune responses. Trends in Immunology. 2012;33:231-237.

    Not in our library10.1016/j.it.2012.02.009 (opens in a new tab)

  13. 13.
    Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy? · 2020
    Not checked
  14. 14.

    Benedicto A, Romayor I, Arteta B. CXCR4 receptor blockage reduces the contribution of tumor and stromal cells to the metastatic growth in the liver. Oncology Reports. 2018;39:2022-2030.

    Not in our library10.3892/or.2018.6254 (opens in a new tab)

  15. 15.

    Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, Washington MK, Neilson EG, Moses HL. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science. 2004;303:848-851.

    Not in our library10.1126/science.1090922 (opens in a new tab)

  16. 16.

    Biffi G, Oni TE, Spielman B, Hao Y, Elyada E, Park Y, Preall J, Tuveson DA. IL1-Induced JAK/STAT signaling is antagonized by tgfβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discovery. 2019;9:282-301.

    Not in our library10.1158/2159-8290.cd-18-0710 (opens in a new tab)

  17. 17.

    Calon A, Lonardo E, Berenguer-Llergo A, Espinet E, Hernando-Momblona X, Iglesias M, Sevillano M, Palomo-Ponce S, Tauriello DV, Byrom D, Cortina C, Morral C, Barceló C, Tosi S, Riera A, Attolini CS, Rossell D, Sancho E, Batlle E. Stromal gene expression defines poor-prognosis subtypes in colorectal Cancer. Nature Genetics. 2015;47:320-329.

    Not in our library10.1038/ng.3225 (opens in a new tab)

  18. 18.

    Castellanos JR, Purvis IJ, Labak CM, Guda MR, Tsung AJ, Velpula KK, Asuthkar S. B7-H3 role in the immune landscape of Cancer. American Journal of Clinical and Experimental Immunology. 2017;6:66-75.

    Not in our library

  19. 19.
    TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure · 2018
    No notice
  20. 20.

    Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, Stylianopoulos T, Mousa AS, Han X, Adstamongkonkul P, Popović Z, Huang P, Bawendi MG, Boucher Y, Jain RK. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nature Communications. 2013;4:2516.

    Not in our library10.1038/ncomms3516 (opens in a new tab)

  21. 21.

    Chen M, Xiang R, Wen Y, Xu G, Wang C, Luo S, Yin T, Wei X, Shao B, Liu N, Guo F, Li M, Zhang S, Li M, Ren K, Wang Y, Wei Y. A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts. Scientific Reports. 2015;5:14421.

    Not in our library10.1038/srep14421 (opens in a new tab)

  22. 22.

    Chen IX, Chauhan VP, Posada J, Ng MR, Wu MW, Adstamongkonkul P, Huang P, Lindeman N, Langer R, Jain RK. Blocking CXCR4 alleviates Desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast Cancer. PNAS. 2019a;116:4558-4566.

    Not in our library10.1073/pnas.1815515116 (opens in a new tab)

  23. 23.

    Chen S, Wainwright DA, Wu JD, Wan Y, Matei DE, Zhang Y, Zhang B. CD73: an emerging checkpoint for Cancer immunotherapy. Immunotherapy. 2019b;11:983-997.

    Not in our library10.2217/imt-2018-0200 (opens in a new tab)

  24. 24.

    Cheng JD, Dunbrack RL, Valianou M, Rogatko A, Alpaugh RK, Weiner LM. Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model. Cancer Research. 2002;62:4767-4772.

    Not in our library

  25. 25.
    Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation · 2016
    No notice
  26. 26.
    Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma · 2018
    No notice
  27. 27.

    Cho Y-A, Yoon H-J, Lee J-I, Hong S-P, Hong S-D. Relationship between the expressions of PD-L1 and tumor-infiltrating lymphocytes in oral squamous cell carcinoma. Oral Oncology. 2011;47:1148-1153.

    Not in our library10.1016/j.oraloncology.2011.08.007 (opens in a new tab)

  28. 28.

    Chomarat P, Banchereau J, Davoust J, Karolina Palucka A, Palucka AK. IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nature Immunology. 2000;1:510-514.

    Not in our library10.1038/82763 (opens in a new tab)

  29. 29.

    Cohen N, Shani O, Raz Y, Sharon Y, Hoffman D, Abramovitz L, Erez N. Fibroblasts drive an immunosuppressive and growth-promoting microenvironment in breast cancer via secretion of Chitinase 3-like 1. Oncogene. 2017;36:4457-4468.

    Not in our library10.1038/onc.2017.65 (opens in a new tab)

  30. 30.

    Colak S, ten Dijke P. Targeting TGF-β Signaling in Cancer. Trends in Cancer. 2017;3:56-71.

    Not in our library10.1016/j.trecan.2016.11.008 (opens in a new tab)

  31. 31.

    Comito G, Giannoni E, Segura CP, Barcellos-de-Souza P, Raspollini MR, Baroni G, Lanciotti M, Serni S, Chiarugi P. Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression. Oncogene. 2014;33:2423-2431.

    Not in our library10.1038/onc.2013.191 (opens in a new tab)

  32. 32.

    Costa A, Kieffer Y, Scholer-Dahirel A, Pelon F, Bourachot B, Cardon M, Sirven P, Magagna I, Fuhrmann L, Bernard C, Bonneau C, Kondratova M, Kuperstein I, Zinovyev A, Givel AM, Parrini MC, Soumelis V, Vincent-Salomon A, Mechta-Grigoriou F. Fibroblast heterogeneity and immunosuppressive environment in human breast Cancer. Cancer Cell. 2018;33:463-479.

    Not in our library10.1016/j.ccell.2018.01.011 (opens in a new tab)

  33. 33.

    Cox TR, Erler JT. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and Cancer. Disease Models & Mechanisms. 2011;4:165-178.

    Not in our library10.1242/dmm.004077 (opens in a new tab)

  34. 34.

    Cremasco V, Astarita JL, Grauel AL, Keerthivasan S, MacIsaac K, Woodruff MC, Wu M, Spel L, Santoro S, Amoozgar Z, Laszewski T, Migoni SC, Knoblich K, Fletcher AL, LaFleur M, Wucherpfennig KW, Pure E, Dranoff G, Carroll MC, Turley SJ. FAP delineates heterogeneous and functionally divergent stromal cells in Immune-Excluded breast tumors. Cancer Immunology Research. 2018;6:1472-1485.

    Not in our library10.1158/2326-6066.cir-18-0098 (opens in a new tab)

  35. 35.

    Dabbous MK, North SM, Haney L, Tipton DA, Nicolson GL. Effects of mast cell-macrophage interactions on the production of collagenolytic enzymes by metastatic tumor cells and tumor-derived and stromal fibroblasts. Clinical & Experimental Metastasis. 1995;13:33-41.

    Not in our library10.1007/bf00144016 (opens in a new tab)

  36. 36.

    Darby IA, Laverdet B, Bonté F, Desmoulière A. Fibroblasts and myofibroblasts in wound healing. Clinical, Cosmetic and Investigational Dermatology. 2014;7:301-311.

    Not in our library10.2147/ccid.s50046 (opens in a new tab)

  37. 37.

    Darby IA, Hewitson TD. Fibroblast differentiation in wound healing and fibrosis. International Review of Cytology. 2007;257:143-179.

    Not in our library10.1016/s0074-7696(07)57004-x (opens in a new tab)

  38. 38.

    de Gramont A, Faivre S, Raymond E. Novel TGF-β inhibitors ready for prime time in onco-immunology. OncoImmunology. 2017;6:e1257453.

    Not in our library10.1080/2162402x.2016.1257453 (opens in a new tab)

  39. 39.

    Deng Y, Cheng J, Fu B, Liu W, Chen G, Zhang Q, Yang Y. Hepatic carcinoma-associated fibroblasts enhance immune suppression by facilitating the generation of myeloid-derived suppressor cells. Oncogene. 2017;36:1090-1101.

    Not in our library10.1038/onc.2016.273 (opens in a new tab)

  40. 40.

    Diaz-Montero CM, Finke J, Montero AJ. Myeloid-derived suppressor cells in Cancer: therapeutic, predictive, and prognostic implications. Seminars in Oncology. 2014;41:174-184.

    Not in our library10.1053/j.seminoncol.2014.02.003 (opens in a new tab)

  41. 41.

    Dominguez CX, Müller S, Keerthivasan S, Koeppen H, Hung J, Gierke S, Breart B, Foreman O, Bainbridge TW, Castiglioni A, Senbabaoglu Y, Modrusan Z, Liang Y, Junttila MR, Klijn C, Bourgon R, Turley SJ. Single-Cell RNA sequencing reveals stromal evolution into LRRC15+ Myofibroblasts as a Determinant of Patient Response to Cancer Immunotherapy. Cancer Discovery. 2020;10:232-253.

    Not in our library10.1158/2159-8290.cd-19-0644 (opens in a new tab)

  42. 42.
    Cancer-Associated Fibroblasts-Derived Exosomes Suppress Immune Cell Function in Breast Cancer via the miR-92/PD-L1 Pathway · 2020
    Retracted
  43. 43.

    Ellem SJ, Taylor RA, Furic L, Larsson O, Frydenberg M, Pook D, Pedersen J, Cawsey B, Trotta A, Need E, Buchanan G, Risbridger GP. A pro-tumourigenic loop at the human prostate tumour interface orchestrated by oestrogen, CXCL12 and mast cell recruitment. The Journal of Pathology. 2014;234:86-98.

    Not in our library10.1002/path.4386 (opens in a new tab)

  44. 44.

    Elyada E, Bolisetty M, Laise P, Flynn WF, Courtois ET, Burkhart RA, Teinor JA, Belleau P, Biffi G, Lucito MS, Sivajothi S, Armstrong TD, Engle DD, Yu KH, Hao Y, Wolfgang CL, Park Y, Preall J, Jaffee EM, Califano A, Robson P, Tuveson DA. Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts. Cancer Discovery. 2019;9:1102-1123.

    Not in our library10.1158/2159-8290.cd-19-0094 (opens in a new tab)

  45. 45.
    NLRP3 inflammasome in fibroblasts links tissue damage with inflammation in breast cancer progression and metastasis · 2019
    No notice
  46. 46.

    Fabre M, Ferrer C, Domínguez-Hormaetxe S, Bockorny B, Murias L, Seifert O, Eisler SA, Kontermann RE, Pfizenmaier K, Lee SY, Vivanco MD, López-Casas PP, Perea S, Abbas M, Richter W, Simon L, Hidalgo M. OMTX705, a novel FAP-Targeting ADC demonstrates activity in chemotherapy and Pembrolizumab-Resistant solid tumor models. Clinical Cancer Research. 2020;26:3420-3430.

    Not in our library10.1158/1078-0432.ccr-19-2238 (opens in a new tab)

  47. 47.

    Farahani RM, Xaymardan M. Platelet-Derived growth factor receptor alpha as a marker of mesenchymal stem cells in development and stem cell biology. Stem Cells International. 2015;2015:1-8.

    Not in our library10.1155/2015/362753 (opens in a new tab)

  48. 48.

    Fearon DT. The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunology Research. 2014;2:187-193.

    Not in our library10.1158/2326-6066.cir-14-0002 (opens in a new tab)

  49. 49.

    Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL, Teichmann SA, Janowitz T, Jodrell DI, Tuveson DA, Fearon DT. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic Cancer. PNAS. 2013;110:20212-20217.

    Not in our library10.1073/pnas.1320318110 (opens in a new tab)

  50. 50.

    Ford K, Hanley CJ, Mellone M, Szyndralewiez C, Heitz F, Wiesel P, Wood O, Machado M, Lopez MA, Ganesan AP, Wang C, Chakravarthy A, Fenton TR, King EV, Vijayanand P, Ottensmeier CH, Al-Shamkhani A, Savelyeva N, Thomas GJ. NOX4 inhibition potentiates immunotherapy by overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell exclusion from tumors. Cancer Research. 2020;80:1846-1860.

    Not in our library10.1158/0008-5472.can-19-3158 (opens in a new tab)

  51. 51.

    Fountzilas C, Javle M, Tan W, Ma Y, Fetterly G, Iyer R, Johnson C. A phase 1, open-label, dose escalation study of intravenous paricalcitol in combination with gemcitabine in patients with advanced malignancies. Cancer. 2018;124:3890-3899.

    Not in our library10.1002/cncr.31676 (opens in a new tab)

  52. 52.

    Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nature Reviews Immunology. 2009;9:162-174.

    Not in our library10.1038/nri2506 (opens in a new tab)

  53. 53.
    Differential Contribution of Pancreatic Fibroblast Subsets to the Pancreatic Cancer StromaSummary · 2020
    Not checked
  54. 54.

    Gardner H, Strehlow D, Bradley L, Widom R, Farina A, de Fougerolles A, Peyman J, Koteliansky V, Korn JH. Global expression analysis of the fibroblast transcriptional response to TGFbeta. Clinical and Experimental Rheumatology. 2004;22:S47-S57.

    Not in our library

  55. 55.

    Ghebeh H, Dermime S. Comment on "Characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells". The Journal of Immunology. 2007;179:732-733.

    Not in our library10.4049/jimmunol.179.2.732 (opens in a new tab)

  56. 56.
    Cancer associated fibroblasts sculpt tumour microenvironment by recruiting monocytes and inducing immunosuppressive PD-1+ TAMs · 2019
    No notice
  57. 57.
    Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations · 2018
    No notice
  58. 58.
    Th17 Cell Plasticity and Functions in Cancer Immunity · 2015
    No notice
  59. 59.

    Hadjipanayi E, Mudera V, Brown RA. Close dependence of fibroblast proliferation on collagen scaffold matrix stiffness. Journal of Tissue Engineering and Regenerative Medicine. 2009;3:77-84.

    Not in our library10.1002/term.136 (opens in a new tab)

  60. 60.

    Hakim N, Patel R, Devoe C, Saif MW, Northwell Health Cancer Institute and Donald and Barbara Zucker School of Medicine, Hofstra/Northwell, NY, USA. Why HALO 301 failed and implications for treatment of pancreatic Cancer. Pancreas – Open Journal. 2019;3:e1-e4.

    Not in our library10.17140/poj-3-e010 (opens in a new tab)

  61. 61.

    Heichler C, Scheibe K, Schmied A, Geppert CI, Schmid B, Wirtz S, Thoma OM, Kramer V, Waldner MJ, Büttner C, Farin HF, Pešić M, Knieling F, Merkel S, Grüneboom A, Gunzer M, Grützmann R, Rose-John S, Koralov SB, Kollias G, Vieth M, Hartmann A, Greten FR, Neurath MF, Neufert C. STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis. Gut. 2020;69:1269-1282.

    Not in our library10.1136/gutjnl-2019-319200 (opens in a new tab)

  62. 62.

    Helms E, Onate MK, Sherman MH. Fibroblast Heterogeneity in the Pancreatic Tumor Microenvironment. Cancer Discovery. 2020;10:648-656.

    Not in our library10.1158/2159-8290.cd-19-1353 (opens in a new tab)

  63. 63.

    Herrera M, Herrera A, Domínguez G, Silva J, García V, García JM, Gómez I, Soldevilla B, Muñoz C, Provencio M, Campos-Martin Y, García de Herreros A, Casal I, Bonilla F, Peña C. Cancer-associated fibroblast and M2 macrophage markers together predict outcome in colorectal Cancer patients. Cancer Science. 2013;104:437-444.

    Not in our library10.1111/cas.12096 (opens in a new tab)

  64. 64.

    Hingorani SR, Zheng L, Bullock AJ, Seery TE, Harris WP, Sigal DS, Braiteh F, Ritch PS, Zalupski MM, Bahary N, Oberstein PE, Wang-Gillam A, Wu W, Chondros D, Jiang P, Khelifa S, Pu J, Aldrich C, Hendifar AE. HALO 202: randomized phase II study of PEGPH20 plus Nab-Paclitaxel/Gemcitabine versus Nab-Paclitaxel/Gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma. Journal of Clinical Oncology. 2018;36:359-366.

    Not in our library10.1200/jco.2017.74.9564 (opens in a new tab)

  65. 65.

    Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. The American Journal of Pathology. 2007;170:1807-1816.

    Not in our library10.2353/ajpath.2007.070112 (opens in a new tab)

  66. 66.

    Holzinger A, Barden M, Abken H. The growing world of CAR T cell trials: a systematic review. Cancer Immunology, Immunotherapy. 2016;65:1433-1450.

    Not in our library10.1007/s00262-016-1895-5 (opens in a new tab)

  67. 67.

    Hosaka K, Yang Y, Seki T, Fischer C, Dubey O, Fredlund E, Hartman J, Religa P, Morikawa H, Ishii Y, Sasahara M, Larsson O, Cossu G, Cao R, Lim S, Cao Y. Pericyte–fibroblast transition promotes tumor growth and metastasis. PNAS. 2016;113:E5618-E5627.

    Not in our library10.1073/pnas.1608384113 (opens in a new tab)

  68. 68.

    Huynh PT, Beswick EJ, Coronado YA, Johnson P, O'Connell MR, Watts T, Singh P, Qiu S, Morris K, Powell DW, Pinchuk IV. CD90(+) stromal cells are the major source of IL-6, which supports Cancer stem-like cells and inflammation in colorectal Cancer. International Journal of Cancer. 2016;138:1971-1981.

    Not in our library10.1002/ijc.29939 (opens in a new tab)

  69. 69.

    Inoue T, Adachi K, Kawana K, Taguchi A, Nagamatsu T, Fujimoto A, Tomio K, Yamashita A, Eguchi S, Nishida H, Nakamura H, Sato M, Yoshida M, Arimoto T, Wada-Hiraike O, Oda K, Osuga Y, Fujii T. Cancer-associated fibroblast suppresses killing activity of natural killer cells through downregulation of poliovirus receptor (PVR/CD155), a ligand of activating NK receptor. International Journal of Oncology. 2016;49:1297-1304.

    Not in our library10.3892/ijo.2016.3631 (opens in a new tab)

  70. 70.

    Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. PNAS. 2002;99:12293-12297.

    Not in our library10.1073/pnas.192461099 (opens in a new tab)

  71. 71.

    Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status and future directions. The Lancet. 2016;388:518-529.

    Not in our library10.1016/s0140-6736(15)01088-0 (opens in a new tab)

  72. 72.

    Ji T, Zhao Y, Ding Y, Wang J, Zhao R, Lang J, Qin H, Liu X, Shi J, Tao N, Qin Z, Nie G, Zhao Y. Transformable Peptide Nanocarriers for Expeditious Drug Release and Effective Cancer Therapy via Cancer-Associated Fibroblast Activation. Angewandte Chemie International Edition. 2016;55:1050-1055.

    Not in our library10.1002/anie.201506262 (opens in a new tab)

  73. 73.

    June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018;359:1361-1365.

    Not in our library10.1126/science.aar6711 (opens in a new tab)

  74. 74.

    Kai F, Drain AP, Weaver VM. The Extracellular Matrix Modulates the Metastatic Journey. Developmental Cell. 2019;49:332-346.

    Not in our library10.1016/j.devcel.2019.03.026 (opens in a new tab)

  75. 75.
    Defining the Role of Solid Stress and Matrix Stiffness in Cancer Cell Proliferation and Metastasis · 2018
    No notice
  76. 76.

    Kato T, Noma K, Ohara T, Kashima H, Katsura Y, Sato H, Komoto S, Katsube R, Ninomiya T, Tazawa H, Shirakawa Y, Fujiwara T. Cancer-Associated Fibroblasts Affect Intratumoral CD8 + and FoxP3 + T Cells Via IL6 in the Tumor Microenvironment. Clinical Cancer Research. 2018;24:4820-4833.

    Not in our library10.1158/1078-0432.ccr-18-0205 (opens in a new tab)

  77. 77.

    Katoh H, Hosono K, Ito Y, Suzuki T, Ogawa Y, Kubo H, Kamata H, Mishima T, Tamaki H, Sakagami H, Sugimoto Y, Narumiya S, Watanabe M, Majima M. COX-2 and prostaglandin EP3/EP4 signaling regulate the tumor stromal proangiogenic microenvironment via CXCL12-CXCR4 chemokine systems. The American Journal of Pathology. 2010;176:1469-1483.

    Not in our library10.2353/ajpath.2010.090607 (opens in a new tab)

  78. 78.

    Kerrigan AM, Navarro-Nuñez L, Pyz E, Finney BA, Willment JA, Watson SP, Brown GD. Podoplanin-expressing inflammatory macrophages activate murine platelets via CLEC-2. Journal of Thrombosis and Haemostasis. 2012;10:484-486.

    Not in our library10.1111/j.1538-7836.2011.04614.x (opens in a new tab)

  79. 79.

    Kinoshita T, Ishii G, Hiraoka N, Hirayama S, Yamauchi C, Aokage K, Hishida T, Yoshida J, Nagai K, Ochiai A. Forkhead box P3 regulatory T cells coexisting with cancer associated fibroblasts are correlated with a poor outcome in lung adenocarcinoma. Cancer Science. 2013;104:409-415.

    Not in our library10.1111/cas.12099 (opens in a new tab)

  80. 80.

    Kiss M, Van Gassen S, Movahedi K, Saeys Y, Laoui D. Myeloid cell heterogeneity in cancer: not a single cell alike. Cellular Immunology. 2018;330:188-201.

    Not in our library10.1016/j.cellimm.2018.02.008 (opens in a new tab)

  81. 81.

    Kitano H. Podoplanin expression in cancerous stroma induces lymphangiogenesis and predicts lymphatic spread and patient survival. Archives of Pathology & Laboratory Medicine. 2010;134:1520-1527.

    Not in our library10.1043/2009-0114-oa.1 (opens in a new tab)

  82. 82.

    Kloss CC, Lee J, Zhang A, Chen F, Melenhorst JJ, Lacey SF, Maus MV, Fraietta JA, Zhao Y, June CH. Dominant-Negative TGF-β Receptor Enhances PSMA-Targeted Human CAR T Cell Proliferation And Augments Prostate Cancer Eradication. Molecular Therapy. 2018;26:1855-1866.

    Not in our library10.1016/j.ymthe.2018.05.003 (opens in a new tab)

  83. 83.

    Ko AH, LoConte N, Tempero MA, Walker EJ, Kate Kelley R, Lewis S, Chang W-C, Kantoff E, Vannier MW, Catenacci DV, Venook AP, Kindler HL. A Phase I Study of FOLFIRINOX Plus IPI-926, a Hedgehog Pathway Inhibitor, for Advanced Pancreatic Adenocarcinoma. Pancreas. 2016;45:370-375.

    Not in our library10.1097/mpa.0000000000000458 (opens in a new tab)

  84. 84.

    Kojima Y, Acar A, Eaton EN, Mellody KT, Scheel C, Ben-Porath I, Onder TT, Wang ZC, Richardson AL, Weinberg RA, Orimo A. Autocrine TGF- and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. PNAS. 2010;107:20009-20014.

    Not in our library10.1073/pnas.1013805107 (opens in a new tab)

  85. 85.

    Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, Tanaka S, Bluestone JA, Takayanagi H. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nature Medicine. 2014;20:62-68.

    Not in our library10.1038/nm.3432 (opens in a new tab)

  86. 86.

    Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 2010;330:827-830.

    Not in our library10.1126/science.1195300 (opens in a new tab)

  87. 87.

    Kumar V, Donthireddy L, Marvel D, Condamine T, Wang F, Lavilla-Alonso S, Hashimoto A, Vonteddu P, Behera R, Goins MA, Mulligan C, Nam B, Hockstein N, Denstman F, Shakamuri S, Speicher DW, Weeraratna AT, Chao T, Vonderheide RH, Languino LR, Ordentlich P, Liu Q, Xu X, Lo A, Puré E, Zhang C, Loboda A, Sepulveda MA, Snyder LA, Gabrilovich DI. Cancer-Associated fibroblasts neutralize the Anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell. 2017;32:654-668.

    Not in our library10.1016/j.ccell.2017.10.005 (opens in a new tab)

  88. 88.

    Kuzet S-E, Gaggioli C. Fibroblast activation in cancer: when seed fertilizes soil. Cell and Tissue Research. 2016;365:607-619.

    Not in our library10.1007/s00441-016-2467-x (opens in a new tab)

  89. 89.
    Cancer-associated fibroblasts induce antigen-specific deletion of CD8 + T Cells to protect tumour cells · 2018
    No notice
  90. 90.

    Lambrechts D, Wauters E, Boeckx B, Aibar S, Nittner D, Burton O, Bassez A, Decaluwé H, Pircher A, Van den Eynde K, Weynand B, Verbeken E, De Leyn P, Liston A, Vansteenkiste J, Carmeliet P, Aerts S, Thienpont B. Phenotype molding of stromal cells in the lung tumor microenvironment. Nature Medicine. 2018;24:1277-1289.

    Not in our library10.1038/s41591-018-0096-5 (opens in a new tab)

  91. 91.

    Lazennec G, Richmond A. Chemokines and chemokine receptors: new insights into cancer-related inflammation. Trends in Molecular Medicine. 2010;16:133-144.

    Not in our library10.1016/j.molmed.2010.01.003 (opens in a new tab)

  92. 92.

    Leach DR, Krummel MF, Allison JP. Enhancement of Antitumor Immunity by CTLA-4 Blockade. Science. 1996;271:1734-1736.

    Not in our library10.1126/science.271.5256.1734 (opens in a new tab)

  93. 93.

    LeBleu VS, Taduri G, O'Connell J, Teng Y, Cooke VG, Woda C, Sugimoto H, Kalluri R. Origin and function of myofibroblasts in kidney fibrosis. Nature Medicine. 2013;19:1047-1053.

    Not in our library10.1038/nm.3218 (opens in a new tab)

  94. 94.
    FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells · 2011
    No notice
  95. 95.

    Li T, Yang Y, Hua X, Wang G, Liu W, Jia C, Tai Y, Zhang Q, Chen G. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Letters. 2012;318:154-161.

    Not in our library10.1016/j.canlet.2011.12.020 (opens in a new tab)

  96. 96.

    Li T, Yi S, Liu W, Jia C, Wang G, Hua X, Tai Y, Zhang Q, Chen G. Colorectal carcinoma-derived fibroblasts modulate natural killer cell phenotype and antitumor cytotoxicity. Medical Oncology. 2013;30:663.

    Not in our library10.1007/s12032-013-0663-z (opens in a new tab)

  97. 97.

    Li H, Courtois ET, Sengupta D, Tan Y, Chen KH, Goh JJL, Kong SL, Chua C, Hon LK, Tan WS, Wong M, Choi PJ, Wee LJK, Hillmer AM, Tan IB, Robson P, Prabhakar S. Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nature Genetics. 2017;49:708-718.

    Not in our library10.1038/ng.3818 (opens in a new tab)

  98. 98.

    Li Z, Zhou J, Zhang J, Li S, Wang H, Du J. Cancer-associated fibroblasts promote PD-L1 expression in mice Cancer cells via secreting CXCL5. International Journal of Cancer. 2019;145:1946-1957.

    Not in our library10.1002/ijc.32278 (opens in a new tab)

  99. 99.

    Li S, Zhao W, Sun M. An analysis regarding the association between the ISLR Gene and Gastric Carcinogenesis. Frontiers in Genetics. 2020;11:620.

    Not in our library10.3389/fgene.2020.00620 (opens in a new tab)

  100. 100.
    Cancer Associated Fibroblasts Promote Tumor Growth and Metastasis by Modulating the Tumor Immune Microenvironment in a 4T1 Murine Breast Cancer Model · 2009
    No notice
  101. 101.

    Lin H-M, Lee BY, Castillo L, Spielman C, Grogan J, Yeung NK, Kench JG, Stricker PD, Haynes A-M, Centenera MM, Butler LM, Shreeve SM, Horvath LG, Daly RJ. Effect of FAK inhibitor VS-6063 (defactinib) on docetaxel efficacy in prostate cancer. The Prostate. 2018;78:308-317.

    Not in our library10.1002/pros.23476 (opens in a new tab)

  102. 102.

    Lo A, Wang L-CS, Scholler J, Monslow J, Avery D, Newick K, O'Brien S, Evans RA, Bajor DJ, Clendenin C, Durham AC, Buza EL, Vonderheide RH, June CH, Albelda SM, Pure E. Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells. Cancer Research. 2015;75:2800-2810.

    Not in our library10.1158/0008-5472.can-14-3041 (opens in a new tab)

  103. 103.

    Lo A, Li CP, Buza EL, Blomberg R, Govindaraju P, Avery D, Monslow J, Hsiao M, Puré E. Fibroblast activation protein augments progression and metastasis of pancreatic ductal adenocarcinoma. JCI Insight. 2017;2:92232.

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    Löhr M, Schmidt C, Ringel J, Kluth M, Müller P, Nizze H, Jesnowski R. Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Research. 2001;61:550-555.

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  105. 105.
    Increased intratumoral mast cells foster immune suppression and gastric cancer progression through TNF-α-PD-L1 pathway · 2019
    Corrected
  106. 106.

    Mace TA, Ameen Z, Collins A, Wojcik S, Mair M, Young GS, Fuchs JR, Eubank TD, Frankel WL, Bekaii-Saab T, Bloomston M, Lesinski GB. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Research. 2013;73:3007-3018.

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  107. 107.

    MacGregor HL, Sayad A, Elia A, Wang BX, Katz SR, Shaw PA, Clarke BA, Crome SQ, Robert-Tissot C, Bernardini MQ, Nguyen LT, Ohashi PS. High expression of B7-H3 on stromal cells defines tumor and stromal compartments in epithelial ovarian Cancer and is associated with limited immune activation. Journal for ImmunoTherapy of Cancer. 2019;7:357.

    Not in our library10.1186/s40425-019-0816-5 (opens in a new tab)

  108. 108.

    Maeda K, Enomoto A, Hara A, Asai N, Kobayashi T, Horinouchi A, Maruyama S, Ishikawa Y, Nishiyama T, Kiyoi H, Kato T, Ando K, Weng L, Mii S, Asai M, Mizutani Y, Watanabe O, Hirooka Y, Goto H, Takahashi M. Identification of meflin as a potential marker for mesenchymal stromal cells. Scientific Reports. 2016;6:22288.

    Not in our library10.1038/srep22288 (opens in a new tab)

  109. 109.

    Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, Kadel EE, Koeppen H, Astarita JL, Cubas R, Jhunjhunwala S, Banchereau R, Yang Y, Guan Y, Chalouni C, Ziai J, Şenbabaoğlu Y, Santoro S, Sheinson D, Hung J, Giltnane JM, Pierce AA, Mesh K, Lianoglou S, Riegler J, Carano RAD, Eriksson P, Höglund M, Somarriba L, Halligan DL, van der Heijden MS, Loriot Y, Rosenberg JE, Fong L, Mellman I, Chen DS, Green M, Derleth C, Fine GD, Hegde PS, Bourgon R, Powles T. Tgfβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554:544-548.

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  110. 110.

    Marsh T, Pietras K, McAllister SS. Fibroblasts as architects of Cancer pathogenesis. Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease. 2013;1832:1070-1078.

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  111. 111.

    Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, Hwu P, Restifo NP, Overwijk WW, Dong C. T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity. 2009;31:787-798.

    Not in our library10.1016/j.immuni.2009.09.014 (opens in a new tab)

  112. 112.

    Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood. 2014;123:2625-2635.

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  113. 113.

    Melief CJM, van Hall T, Arens R, Ossendorp F, van der Burg SH. Therapeutic cancer vaccines. Journal of Clinical Investigation. 2015;125:3401-3412.

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  114. 114.

    Midgley AC, Rogers M, Hallett MB, Clayton A, Bowen T, Phillips AO, Steadman R. Transforming growth Factor-β1 (TGF-β1)-stimulated fibroblast to myofibroblast differentiation is mediated by hyaluronan (HA)-facilitated epidermal growth factor receptor (EGFR) and CD44 Co-localization in lipid rafts. Journal of Biological Chemistry. 2013;288:14824-14838.

    Not in our library10.1074/jbc.m113.451336 (opens in a new tab)

  115. 115.

    Mizutani Y, Kobayashi H, Iida T, Asai N, Masamune A, Hara A, Esaki N, Ushida K, Mii S, Shiraki Y, Ando K, Weng L, Ishihara S, Ponik SM, Conklin MW, Haga H, Nagasaka A, Miyata T, Matsuyama M, Kobayashi T, Fujii T, Yamada S, Yamaguchi J, Wang T, Woods SL, Worthley D, Shimamura T, Fujishiro M, Hirooka Y, Enomoto A, Takahashi M. Meflin-Positive Cancer-Associated fibroblasts inhibit pancreatic carcinogenesis. Cancer Research. 2019;79:5367-5381.

    Not in our library10.1158/0008-5472.can-19-0454 (opens in a new tab)

  116. 116.

    Montesano R, Orci L. Transforming growth factor beta stimulates collagen-matrix contraction by fibroblasts: implications for wound healing. PNAS. 1988;85:4894-4897.

    Not in our library10.1073/pnas.85.13.4894 (opens in a new tab)

  117. 117.
    Mechanisms of TGFβ-Induced Epithelial–Mesenchymal Transition · 2016
    No notice
  118. 118.

    Nazareth MR, Broderick L, Simpson-Abelson MR, Kelleher RJ, Yokota SJ, Bankert RB. Characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells. The Journal of Immunology. 2007;178:5552-5562.

    Not in our library10.4049/jimmunol.178.9.5552 (opens in a new tab)

  119. 119.

    Neesse A, Frese KK, Bapiro TE, Nakagawa T, Sternlicht MD, Seeley TW, Pilarsky C, Jodrell DI, Spong SM, Tuveson DA. CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas Cancer. PNAS. 2013;110:12325-12330.

    Not in our library10.1073/pnas.1300415110 (opens in a new tab)

  120. 120.

    Nicholson SE, Keating N, Belz GT. Natural killer cells and anti-tumor immunity. Molecular Immunology. 2019;110:40-47.

    Not in our library10.1016/j.molimm.2017.12.002 (opens in a new tab)

  121. 121.

    Nieman KM, Romero IL, Van Houten B, Lengyel E. Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 2013;1831:1533-1541.

    Not in our library10.1016/j.bbalip.2013.02.010 (opens in a new tab)

  122. 122.

    Nishina T, Takahashi S, Iwasawa R, Noguchi H, Aoki M, Doi T. Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors. Investigational New Drugs. 2018;36:424-434.

    Not in our library10.1007/s10637-017-0514-4 (opens in a new tab)

  123. 123.

    NOXXON Pharma AG. NOX-A12 multiple ascending dose study in healthy volunteers (SNOXA12C101). 2010.

    Not in our library

  124. 124.

    NOXXON Pharma AG. Olaptesed (NOX-A12) Alone and in combination with pembrolizumab in colorectal and pancreatic Cancer (Keynote-559). 2017.

    Not in our library

  125. 125.

    NOXXON Pharma AG. Glioblastoma treatment with irradiation and olaptesed pegol (NOX-A12) in MGMT unmethylated patients (GLORIA). 2019.

    Not in our library

  126. 126.

    Numasaki M. Interleukin-17 promotes angiogenesis and tumor growth. Blood. 2003;101:2620-2627.

    Not in our library10.1182/blood-2002-05-1461 (opens in a new tab)

  127. 127.

    Nurmik M, Ullmann P, Rodriguez F, Haan S, Letellier E. In search of definitions: Cancer‐associated fibroblasts and their markers. International Journal of Cancer. 2020;146:895-905.

    Not in our library10.1002/ijc.32193 (opens in a new tab)

  128. 128.

    Obermajer N, Muthuswamy R, Odunsi K, Edwards RP, Kalinski P. PGE2-Induced CXCL12 Production and CXCR4 Expression Controls the Accumulation of Human MDSCs in Ovarian Cancer Environment. Cancer Research. 2011;71:7463-7470.

    Not in our library10.1158/0008-5472.can-11-2449 (opens in a new tab)

  129. 129.
    Neutrophils in cancer: prognostic role and therapeutic strategies · 2017
    No notice
  130. 130.
    Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer · 2017
    No notice
  131. 131.

    Österreicher CH, Penz-Österreicher M, Grivennikov SI, Guma M, Koltsova EK, Datz C, Sasik R, Hardiman G, Karin M, Brenner DA. Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. PNAS. 2011;108:308-313.

    Not in our library10.1073/pnas.1017547108 (opens in a new tab)

  132. 132.

    Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, De Jesus-Acosta A, Sharma P, Heidari P, Mahmood U, Chin L, Moses HL, Weaver VM, Maitra A, Allison JP, LeBleu VS, Kalluri R. Depletion of Carcinoma-Associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas Cancer with reduced survival. Cancer Cell. 2015;28:831-833.

    Not in our library10.1016/j.ccell.2015.11.002 (opens in a new tab)

  133. 133.

    Park JE, Lenter MC, Zimmermann RN, Garin-Chesa P, Old LJ, Rettig WJ. Fibroblast Activation Protein, a Dual Specificity Serine Protease Expressed in Reactive Human Tumor Stromal Fibroblasts. Journal of Biological Chemistry. 1999;274:36505-36512.

    Not in our library10.1074/jbc.274.51.36505 (opens in a new tab)

  134. 134.
    LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy · 2019
    No notice
  135. 135.

    Phan SH. The myofibroblast in pulmonary fibrosis. Chest. 2002;122:286S-289.

    Not in our library10.1378/chest.122.6_suppl.286s (opens in a new tab)

  136. 136.
    Spatial and Single-Cell Transcriptional Profiling Identifies Functionally Distinct Human Dermal Fibroblast Subpopulations · 2018
    No notice
  137. 137.

    Pinchuk IV, Saada JI, Beswick EJ, Boya G, Qiu SM, Mifflin RC, Raju GS, Reyes VE, Powell DW. PD-1 ligand expression by human colonic myofibroblasts/fibroblasts regulates CD4+ T-cell activity. Gastroenterology. 2008;135:1228-1237.

    Not in our library10.1053/j.gastro.2008.07.016 (opens in a new tab)

  138. 138.

    Pinchuk IV, Beswick EJ, Saada JI, Boya G, Schmitt D, Raju GS, Brenmoehl J, Rogler G, Reyes VE, Powell DW. Human colonic myofibroblasts promote expansion of CD4+ CD25high Foxp3+ regulatory T cells. Gastroenterology. 2011;140:2019-2030.

    Not in our library10.1053/j.gastro.2011.02.059 (opens in a new tab)

  139. 139.

    Postlethwaite AE, Keski-Oja J, Moses HL, Kang AH. Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta. Journal of Experimental Medicine. 1987;165:251-256.

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  140. 140.

    Puré E, Blomberg R. Pro-tumorigenic roles of fibroblast activation protein in Cancer: back to the basics. Oncogene. 2018;37:4343-4357.

    Not in our library10.1038/s41388-018-0275-3 (opens in a new tab)

  141. 141.

    Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, Dekleva EN, Saunders T, Becerra CP, Tattersall IW, Westphalen CB, Kitajewski J, Fernandez-Barrena MG, Fernandez-Zapico ME, Iacobuzio-Donahue C, Olive KP, Stanger BZ. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014;25:735-747.

    Not in our library10.1016/j.ccr.2014.04.021 (opens in a new tab)

  142. 142.

    Ringuette Goulet C, Bernard G, Tremblay S, Chabaud S, Bolduc S, Pouliot F. Exosomes induce fibroblast differentiation into Cancer-Associated fibroblasts through tgfβ signaling. Molecular Cancer Research. 2018;16:1196-1204.

    Not in our library10.1158/1541-7786.mcr-17-0784 (opens in a new tab)

  143. 143.

    Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective Cancer immunotherapy. Nature Reviews Cancer. 2008;8:299-308.

    Not in our library10.1038/nrc2355 (opens in a new tab)

  144. 144.

    Saetersmoen ML, Hammer Q, Valamehr B, Kaufman DS, Malmberg KJ. Off-the-shelf cell therapy with induced pluripotent stem cell-derived natural killer cells. Seminars in Immunopathology. 2019;41:59-68.

    Not in our library10.1007/s00281-018-0721-x (opens in a new tab)

  145. 145.
    A framework for advancing our understanding of cancer-associated fibroblasts · 2020
    No notice
  146. 146.

    Samoszuk M, Kanakubo E, Chan JK. Degranulating mast cells in fibrotic regions of human tumors and evidence that mast cell heparin interferes with the growth of tumor cells through a mechanism involving fibroblasts. BMC Cancer. 2005;5:121.

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  147. 147.

    Shani O, Vorobyov T, Monteran L, Lavie D, Cohen N, Raz Y, Tsarfaty G, Avivi C, Barshack I, Erez N. Fibroblast-Derived IL33 facilitates breast Cancer metastasis by modifying the immune microenvironment and driving type 2 immunity. Cancer Research. 2020;80:5317-5329.

    Not in our library10.1158/0008-5472.can-20-2116 (opens in a new tab)

  148. 148.

    Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, Tiriac H, Collisson EA, Connor F, Van Dyke T, Kozlov S, Martin P, Tseng TW, Dawson DW, Donahue TR, Masamune A, Shimosegawa T, Apte MV, Wilson JS, Ng B, Lau SL, Gunton JE, Wahl GM, Hunter T, Drebin JA, O'Dwyer PJ, Liddle C, Tuveson DA, Downes M, Evans RM. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic Cancer therapy. Cell. 2014;159:80-93.

    Not in our library10.1016/j.cell.2014.08.007 (opens in a new tab)

  149. 149.

    Shi Y, Gao W, Lytle NK, Huang P, Yuan X, Dann AM, Ridinger-Saison M, DelGiorno KE, Antal CE, Liang G, Atkins AR, Erikson G, Sun H, Meisenhelder J, Terenziani E, Woo G, Fang L, Santisakultarm TP, Manor U, Xu R, Becerra CR, Borazanci E, Von Hoff DD, Grandgenett PM, Hollingsworth MA, Leblanc M, Umetsu SE, Collisson EA, Scadeng M, Lowy AM, Donahue TR, Reya T, Downes M, Evans RM, Wahl GM, Pawson T, Tian R, Hunter T. Targeting LIF-mediated paracrine interaction for pancreatic Cancer therapy and monitoring. Nature. 2019;569:131-135.

    Not in our library10.1038/s41586-019-1130-6 (opens in a new tab)

  150. 150.
    Podoplanin expression in cancer-associated fibroblasts enhances tumor progression of invasive ductal carcinoma of the pancreas · 2013
    No notice
  151. 151.

    Sorokin L. The impact of the extracellular matrix on inflammation. Nature Reviews Immunology. 2010;10:712-723.

    Not in our library10.1038/nri2852 (opens in a new tab)

  152. 152.

    Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomaszewski JE, Neilson EG. Identification and characterization of a fibroblast marker: fsp1. Journal of Cell Biology. 1995;130:393-405.

    Not in our library10.1083/jcb.130.2.393 (opens in a new tab)

  153. 153.

    Sugimoto H, Mundel TM, Kieran MW, Kalluri R. Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biology & Therapy. 2006;5:1640-1646.

    Not in our library10.4161/cbt.5.12.3354 (opens in a new tab)

  154. 154.
    Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages · 2016
    No notice
  155. 155.

    Takehara K. Growth regulation of skin fibroblasts. Journal of Dermatological Science. 2000;24 Suppl 1:S70-S77.

    Not in our library10.1016/s0923-1811(00)00144-4 (opens in a new tab)

  156. 156.

    Takesue S, Ohuchida K, Shinkawa T, Otsubo Y, Matsumoto S, Sagara A, Yonenaga A, Ando Y, Kibe S, Nakayama H, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Toma H, Tominaga Y, Mizumoto K, Hashizume M, Nakamura M. Neutrophil extracellular traps promote liver micrometastasis in pancreatic ductal adenocarcinoma via the activation of cancer–associated fibroblasts. International Journal of Oncology. 2020;56:596-605.

    Not in our library10.3892/ijo.2019.4951 (opens in a new tab)

  157. 157.

    Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, Sevillano M, Ibiza S, Cañellas A, Hernando-Momblona X, Byrom D, Matarin JA, Calon A, Rivas EI, Nebreda AR, Riera A, Attolini CS-O, Batlle E. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018;554:538-543.

    Not in our library10.1038/nature25492 (opens in a new tab)

  158. 158.

    Tejchman A, Lamerant-Fayel N, Jacquinet J-C, Bielawska-Pohl A, Mleczko-Sanecka K, Grillon C, Chouaib S, Ugorski M, Kieda C. Tumor hypoxia modulates podoplanin/CCL21 interactions in CCR7+ NK cell recruitment and CCR7+ tumor cell mobilization. Oncotarget. 2017;8:31876-31887.

    Not in our library10.18632/oncotarget.16311 (opens in a new tab)

  159. 159.

    Thompson CB, Shepard HM, O'Connor PM, Kadhim S, Jiang P, Osgood RJ, Bookbinder LH, Li X, Sugarman BJ, Connor RJ, Nadjsombati S, Frost GI. Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical animal models. Molecular Cancer Therapeutics. 2010;9:3052-3064.

    Not in our library10.1158/1535-7163.mct-10-0470 (opens in a new tab)

  160. 160.

    Varga J, Jimenez SA. Stimulation of normal human fibroblast collagen production and processing by transforming growth factor-beta. Biochemical and Biophysical Research Communications. 1986;138:974-980.

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  161. 161.

    Wang LC, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, Antzis M, Cotner CE, Johnson LA, Durham AC, Solomides CC, June CH, Puré E, Albelda SM. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunology Research. 2014;2:154-166.

    Not in our library10.1158/2326-6066.cir-13-0027 (opens in a new tab)

  162. 162.
    Tumor-Associated Neutrophils in Cancer: Going Pro · 2019
    No notice
  163. 163.

    Yamamoto T, Hartmann K, Eckes B, Krieg T. Mast cells enhance contraction of three-dimensional collagen lattices by fibroblasts by cell-cell interaction: role of stem cell factor/c-kit. Immunology. 2000;99:435-439.

    Not in our library10.1046/j.1365-2567.2000.00973.x (opens in a new tab)

  164. 164.

    Yamauchi M, Gibbons DL, Zong C, Fradette JJ, Bota-Rabassedas N, Kurie JM. Fibroblast heterogeneity and its impact on extracellular matrix and immune landscape remodeling in Cancer. Matrix Biology. 2020;91-92:8-18.

    Not in our library10.1016/j.matbio.2020.05.001 (opens in a new tab)

  165. 165.

    Yang X, Lin Y, Shi Y, Li B, Liu W, Yin W, Dang Y, Chu Y, Fan J, He R. FAP promotes immunosuppression by Cancer-Associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling. Cancer Research. 2016;76:4124-4135.

    Not in our library10.1158/0008-5472.can-15-2973 (opens in a new tab)

  166. 166.
    B7-H3, a checkpoint molecule, as a target for cancer immunotherapy · 2020
    No notice
  167. 167.
    CD73 on cancer-associated fibroblasts enhanced by the A2B-mediated feedforward circuit enforces an immune checkpoint · 2020
    No notice
  168. 168.

    Zboralski D, Hoehlig K, Eulberg D, Frömming A, Vater A. Increasing Tumor-Infiltrating T cells through inhibition of CXCL12 with NOX-A12 synergizes with PD-1 blockade. Cancer Immunology Research. 2017;5:950-956.

    Not in our library10.1158/2326-6066.cir-16-0303 (opens in a new tab)

  169. 169.
    Cancer-associated fibroblasts enhance tumor-associated macrophages enrichment and suppress NK cells function in colorectal cancer · 2019
    No notice
  170. 170.

    Zhang J, Ji C, Li W, Mao Z, Shi Y, Shi H, Ji R, Qian H, Xu W, Zhang X. Tumor-Educated neutrophils activate mesenchymal stem cells to promote gastric Cancer growth and metastasis. Frontiers in Cell and Developmental Biology. 2020;8:788.

    Not in our library10.3389/fcell.2020.00788 (opens in a new tab)

  171. 171.

    Zhou J, Wang XH, Zhao YX, Chen C, Xu XY, Sun Q, Wu HY, Chen M, Sang JF, Su L, Tang XQ, Shi XB, Zhang Y, Yu Q, Yao YZ, Zhang WJ. Cancer-Associated fibroblasts correlate with Tumor-Associated macrophages infiltration and lymphatic metastasis in triple negative breast Cancer patients. Journal of Cancer. 2018;9:4635-4641.

    Not in our library10.7150/jca.28583 (opens in a new tab)

  172. 172.

    Zhu Q, Zhang X, Zhang L, Li W, Wu H, Yuan X, Mao F, Wang M, Zhu W, Qian H, Xu W. The IL-6-STAT3 Axis mediates a reciprocal crosstalk between cancer-derived mesenchymal stem cells and neutrophils to synergistically prompt gastric Cancer progression. Cell Death & Disease. 2014;5:e1295.

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