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Fibrinogen-like protein 1 (FGL1): the next immune checkpoint target

Wenjing Qian, Mingfang Zhao, Ruoyu Wang and 1 more

Journal of Hematology & Oncology · 2021 · Review · CC BY

doi:10.1186/s13045-021-01161-8

Abstract

Immune checkpoint therapy has achieved significant efficacy by blocking inhibitory pathways to release the function of T lymphocytes. In the clinic, anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs) have progressed to first-line monotherapies in certain tumor types. However, the efficacy of anti-PD-1/PD-L1 mAbs is still limited due to toxic side effects and de novo or adaptive resistance. Moreover, other immune checkpoint target and biomarkers for therapeutic response prediction are still lacking; as a biomarker, the PD-L1 (CD274, B7-H1) expression level is not as accurate as required. Hence, it is necessary to seek more representative predictive molecules and potential target molecules for immune checkpoint therapy. Fibrinogen-like protein 1 (FGL1) is a proliferation- and metabolism-related protein secreted by the liver. Multiple studies have confirmed that FGL1 is a newly emerging checkpoint ligand of lymphocyte activation gene 3 (LAG3), emphasizing the potential of targeting FGL1/LAG3 as the next generation of immune checkpoint therapy. In this review, we summarize the substantial regulation mechanisms of FGL1 in physiological and pathological conditions, especially tumor epithelial to mesenchymal transition, immune escape and immune checkpoint blockade resistance, to provide insights for targeting FGL1 in cancer treatment.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 27, 2026. Paragraph numbers are ours, so an answer can point at one.

Background

Immune checkpoints (ICs) are essential in modulating the immune response and mediate T cell dysfunction in autoimmunity and inflammation. However, these inhibitory pathways can be educated by tumor cells and promote tumor immune escape. Recent cancer immune checkpoint blockade therapies have aimed to reverse such T cell exhaustion by targeting immune checkpoints “to release the brakes”, which allows cytotoxic T cells to attack tumor cells. In recent years, targeted cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and/or PD-1/PD-L1 therapies have been used in the treatment of clinically advanced tumors and have achieved high rates of objective remission. Unfortunately, several cancer patients receiving PD-1/PD-L1 mAb therapy have exhibited pseudoprogression (PP) or hyperprogression (HP). Although PP is considered a rare phenomenon with varying incidence rates (approximately 1–10%) in different tumors using different assessment criteria (Response Evaluation Criteria in Solid Tumors (RECIST) and immune-related response criteria (irRC)), anti-PD-1/PD-L1 therapy still needs to be treated with caution to achieve higher survival benefits. Additionally, previous studies reported that 9% of 131 evaluable patients were considered to have HP (defined as a twofold increase in the tumor growth rate between the reference and experimental periods). In addition, patients treated with nivolumab (a humanized mAb against PD-1) were found to be at a higher risk of developing side effects, such as interstitial pneumonia and colitis. Most importantly, it has been confirmed that only 20% of patients benefit from immune checkpoint blockade therapy in clinical studies, with the rest of the patients showing primary or adaptive drug resistance to varying degrees. Therefore, the efficacy of immunotherapy is not satisfactory. Thus, attention has turned to other effective immune checkpoint pathways in further studies.

Recent studies have focused on one of the most promising immune checkpoints. LAG3 (CD223) is an inhibitory receptor expressed mainly on the surface of T lymphocytes. The binding of LAG3 with its ligands delivers negative signals to activated T cells, preventing immune-mediated tissue damage. Similar to PD-1/PD-L1, LAG3 has an inhibitory function based on interactions with its ligands, which include major histocompatibility complex II (MHC II), galectin-3, liver sinusoidal endothelial cell lectin (LSECtin) and FGL1. FGL1, also known as liver fibrinogen-related gene-1 (LFIRE-1)/Hepassocin (HPS) or hepatocyte-derived fibrinogen-related protein-1 (HFREP-1), is a proliferation- and metabolism-related factor secreted by the liver. It has recently emerged as a novel ligand of LAG3 beyond the classic ligand MHC II and can bind with LAG3 to form a new immune checkpoint pathway independent of PD-1/PD-L1, which results in T cell depletion and subsequent dysfunction, as well as tumor cell escape from immune surveillance. Apart from its relatively high expression in the liver and pancreas, FGL1 is upregulated in tumor tissues (including lung, prostate, melanoma, colorectal, breast and brain tumors) based on several datasets. Hence, FGL1 has potential as another immune checkpoint target in clinical practice, especially in targeted therapy for non-small cell lung cancer (NSCLC). In this review, we summarize the function and molecular mechanism of FGL1 in the regulation of cancer development and metastasis and provide promising applications in therapeutic strategies for malignant tumor treatment.

Structure and distribution of FGL1

FGL1 is located on human chromosome 8 (8p22-21.3) and is a 68-KD protein comprised of a disulfide bond-linked homodimer. Its carboxyl terminus contains the β and γ subunits, which are highly homologous to fibrinogen but irrelevant to coagulation-related binding sites. Under normal physiological conditions, FGL1 is secreted mainly by hepatocytes in the liver (some of which may also exist in the pancreas). It is now clear that FGL1 is the product of hepatocyte regeneration and participates in hepatocyte mitosis and liver energy utilization (including lipid metabolism and blood glucose regulation). Apart from the above functions, FGL1 can also be detected in the plasma as an acute reactant, implying that FGL1 secreted by the liver acts not only on hepatocytes (autocrine) but also on other tissues, such as muscle and brown adipose tissues (telecrine) (Fig. 1a). Under stimulation by metabolic factors (hyperglycemia, hyperlipidemia, hormones, etc.), the liver secretes FGL1 and participates in the blood circulation. This function of FGL1 acts on brown adipose tissue, regulates body productivity and maintains body temperature. Moreover, FGL1 also acts on muscle tissue and affects the sensitivity of myoblasts to insulin.

Expression, regulation and function of FGL1 in benign disease

Given that FGL1 is a physiological secretory factor of the liver, its expression can be regarded as a self-protective mechanism acting against exogenous injury or stimulation. FGL1 expression is regulated by radiation-induced lung, liver and stomach injury. In addition, factors released by hepatectomy and postoperative inflammation (interleukin (IL)-6 and transforming growth factor (TGF)-β) can also affect the expression of FGL1. Under such exogenous induction, normal hepatocytes regulate FGL1 transcription via signal transducer and activator of transcription 3 (STAT3) and hepatocyte nuclear factor-1α (HNF-1α) (Fig. 1b). FGL1 expression can also be regulated in chronic medical diseases, such as hyperlipidemia, insulin resistance, and hyperglycemia crisis. Hitherto, there have been studies on the mechanism of the FGL1-mediated regulation of substance metabolism in chronic diseases (Table 1). In clinical practice, changes in the FGL1 expression level can be specifically observed in type 2 diabetes patients with non-alcoholic liver disease. Recently, plasma tests in these patients have found that FGL1 is upregulated when insulin resistance occurs. The high concentration of FGL1 in the plasma acts not only on itself but also on both adipocytes and myoblasts (Fig. 1a). In a hyperlipidemic model, palmitate-treated primary hepatocytes regulated the expression of FGL1 through CCAAT/enhancer-binding protein β (C/EBPβ)-mediated transcription, and the expression level of FGL1 in the liver of mice fed a high-fat diet (HFD) was also increased. This high level of FGL1 could act on C2C12 cells (myoblasts) and generate insulin resistance through the phosphorylated JNK pathway. In addition, in patients with type 2 diabetes, FGL1 induces insulin resistance in HepG2 cells via the hepatocyte-dependent extracellular regulated protein kinase (ERK)1/2 pathway. Furthermore, in adipocytes, extracellular FGL1 induces adipogenesis through the canonical ERK1/2-C/EBPβ-peroxisome proliferator-activated receptor (PPAR) γ pathway.

Apart from protecting hepatocytes (promoting regeneration and apoptosis) and regulating metabolism, FGL1 expression can also be used as a marker of some benign diseases (autoimmunity, infectious diseases, acute inflammation, etc.). First, the value of FGL1 can predict the activity of rheumatoid arthritis (RA; moderate/high: 91.46%; remission/low: 80.77%) and the severity of dengue fever. Second, the fluctuation in FGL1 expression in vivo can also affect the progression of obesity and malaria parasite infection. These above studies reveal that FGL1 plays important roles and acts as a potential biomarker in several common benign diseases.

FGL1 is upregulated in solid tumors

At present, studies on the regulation of FGL1 expression are not limited to the exploration of its physiological and pathological functions. The expression of FGL1 in human solid tumors is different from that in paracancerous tissues. According to the bioGPS tissue microarray database and a proteomic analysis, both the mRNA and protein expression levels of FGL1 are mainly confined to the normal liver and pancreas in humans. A meta-analysis of Oncomine datasets showed that FGL1 expression was upregulated in lung, prostate, melanoma, colorectal, breast cancer and brain tumors but downregulated in pancreatic, breast, liver and head and neck cancers. Among these changes, the trends observed in lung, prostate and liver tumors were consistent with those in The Cancer Genome Atlas (TCGA) datasets, while FGL1 was significantly upregulated in the lung adenocarcinoma cancer map (FGL1 ranked 38th among the top 200 highly expressed genes in lung cancer). In addition, multiple quantitative immunofluorescence (QIF) staining was performed on a tissue microarray of 275 NSCLC samples to detect FGL1 protein expression in cells and tissues (Table 2). The data showed that the FGL1 protein was expressed in local pan-keratin-positive tumor cells but the stromal compartment exhibited almost no expression. These above results indicate that the expression of FGL1 is upregulated in human tumors, as represented by NSCLC. Moreover, FGL1 is downregulated in hepatocellular carcinoma (HCC) in TCGA datasets. This result was also confirmed in a recent study showing that the expression of FGL1 could be downregulated due to the deletion of HNF1α in HCC (Fig. 1c). Hence, FGL1 is released at lower levels by HCC tumor tissues but at higher levels in other solid tumors.

FGL1 mediates EMT process in tumors

The process of tumor progression is accompanied by changes in angiogenesis, invasion and migration. Tumor epithelial to mesenchymal transition (EMT) is not only reflected in changes in cell morphology but also closely related to the behaviors of tumor cell invasion and migration. Previous preclinical studies have confirmed the correlation between FGL1 and the tumor EMT process in lung and gastric cancers. First, following FGL1 silencing in liver kinase B1 (LKB1)-mutant lung adenocarcinoma cells (A549 and H157 cells), E-cadherin was shown to be downregulated, while N-cadherin and vimentin were upregulated. However, another opposite conclusion was also reached: E-cadherin was upregulated and the expression of N-cadherin and vimentin was suppressed when FGL1 was knocked out in SGC-7901 gastric cancer cells. Hence, the relationship between FGL1 and EMT progression in tumor cells still needs to be further investigated. In addition, a correlation between FGL1 and the EMT process has also been reported in a pulmonary fibrosis model, which is distinct from tumor models. Knockout of FGL1 impeded the processes of radiation- or TGF-β-induced EMT. After silencing the FGL1 gene in L132 cells, EMT markers (increased: Snail, Twist, MMP12 and fibronectin; decreased: ZO-1) changed at both the mRNA and protein levels. These above studies demonstrate that there is a correlation between FGL1 and the EMT process in tumors but the conclusions are not consistent. In the presence of FGL1, interstitial markers are downregulated, confirming that FGL1 modulates EMT under radiation or inflammatory induction. This effect may be closely related to the protective effect of FGL1 in response to injury stimulation. As tumor EMT is tightly associated with prognosis and drug resistance, the specific mechanism by which FGL1 regulates tumor EMT needs to be clarified (Fig. 2).

FGL1 regulates other tumor characteristics

Apart from mediating the EMT process, FGL1 is also involved in tumor proliferation, apoptosis, radiation and drug sensitivity. Tumor growth is closely correlated with cell proliferation and apoptosis. The clonal proliferation ability of PC9/GR cells was evaluated in a study on targeted drug resistance in NSCLC, and the data showed that the proliferation of PC9/GR cells decreased significantly after FGL1 silencing. Knockout of FGL1 could significantly dampen the proliferation of SGC-7901 cells. It has been reported that the activation of mTOR is tightly related to the proliferation of HCC cells. As an inhibitor of HCC, FGL1 regulates the occurrence of HCC mainly by inhibiting AKT and downstream pathways, indicating that AKT-mTOR is an important pathway downstream of FGL1 involved in regulating cell proliferation. On the other hand, in the mechanism of FGL1-mediated gefitinib resistance, FGL1 was found to regulate apoptosis through the PARP1/caspase-3 pathway, which also confirmed that FGL1 is pertinent to the sensitivity of tumor cells to targeted EGFR-tyrosine kinase inhibitors (TKIs) (Fig. 2). A recent study on FGL1-mediated targeted therapy resistance have also been reported in HCC. In addition, although FGL1 is a mediator of radiation injury, the correlation between FGL1 and radiation sensitivity needs to be confirmed by additional studies.

FGL1 and tumor immune escape

In the tumor microenvironment (TME), some tumor and regulatory immune cells, such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), immature dendritic cells (iDCs) have the ability to generate inhibitory molecules (like TIM3, TIGIT and VISTA), which can bind receptors on immune cells (NK cells, lymphocytes, etc.), reducing the toxicity of immune responses and thus contributing to immune escape. These molecules play important roles in antitumor efficacy and outcome prediction. The most representative immune checkpoint targets are PD-1 and PD-L1. More recently, Chen and his coworkers have elucidated that the FGL1/LAG3 pathway is another encouraging immune checkpoint pathway that plays a crucial role in the immune escape mechanism, similar to PD-1/PD-L1, and potentially mediates resistance to anti-PD-1/PD-L1 therapy. Thus, as a LAG3 ligand, FGL1 will be another promising biomarker with predictive value for PD-1/PD-L1 resistance.

FGL1 is a major immune inhibitory ligand of LAG3

FGL1 was first identified as a new high-affinity ligand for the inhibitory receptor LAG3 by Dr. Chen’s team in 2019. LAG3 is a type I transmembrane protein that exists mainly on the surface of activated T cells (including CD4+ and CD8+ T cells and Tregs), NK cells, plasmacytoid dendritic cells (pDCs), and so on. The extracellular domain of LAG3 is 20% similar to that of CD4, which determines the high affinity between LAG3 and MHC II. LAG3 interacts with MHC II and generates a negative signal (blocking the TCR activation signal) to restrict T helper 1 (Th1) cell activation, proliferation and secretion. Conversely, activated T cells expressing LAG3 stimulate the production of cytokines (tumor necrosis factor (TNF)-α and IL-12) in antigen-presenting cells (APCs) (DCs and monocytes) and induce their maturation and activation. Notably, researchers found that junction peptides between the D4 transmembrane region and transmembrane region could be cleaved to generate soluble LAG3 (s-LAG3), which could activate thymic epithelial cells and increase CD4+ T cell levels through the transduction of MHC II signals (Fig. 3).

In some subsequent studies, it was confirmed that MHC II is not the only ligand of LAG3. Most recently, evidence has demonstrated that FGL1 is another type of high-affinity immunosuppressive ligand that binds to LAG3. A number of basic research studies have revealed that there is a high-affinity interaction between LAG3 and FGL1. In the Genome-Scale Receptor Array (GSRA) system, FGL1 was the main binding protein of LAG3-Ig, and the interaction between them was stable, specific and conserved across species. A further domain deletion study showed that the fibrinogen-like domain (FD) in FGL1 and the D1-D2 domain in LAG3 are involved in the MHC II-independent interaction between FGL1 and LAG3. Based on in vivo experiments, loss of the FGL1/LAG3 interaction could be achieved by gene knockout or antibody blockade, and antitumor immunity could be promoted by stimulating tumor-infiltrating lymphocyte (TIL) activation and expansion in the TME.

Synergistic inhibition of T cells with PD-1 and FGL1 as a LAG3 ligand

Although the specific mechanism by which FGL1/LAG3 modulates T cell functions remains unclear, the synergistic inhibitory effect of FGL1 blockade in conjunction with anti-PD-1 therapy has been confirmed in animal models. It has been indicated that blocking FGL1 can cooperate with anti-PD-1/PD-L1 therapy to suppress the effect of PD-1/PD-L1 signaling, which is based on previous basic research studies on the synergistic inhibitory activities. The synergistic inhibitory effect of LAG3 and PD-1 on T cells has been confirmed in a variety of tumors, including NSCLC, melanoma, renal cell carcinoma (RCC), head and neck cancer, and breast cancer. Among these diseases, melanoma shows a close relationship between the coexpression of the immune checkpoint molecules LAG3 and PD-1 and the expression of CD163 and density of TAMs. These preclinical results have paved the way for combinatorial blockade of PD-1 and LAG3 in clinical trials. Most importantly, FGL1 will be a potential biomarker for predicting the outcome of PD-1/PD-L1 blockade therapy, since high plasma FGL1 levels were reported to be significantly correlated with a worse therapeutic response to anti-PD-1/PD-L1 therapy in NSCLC and melanoma patients. Therefore, FGL1 can be identified as a next-generation cancer immunotherapy target capable of a functional interaction with the LAG3 pathway and synergistic inhibition of T cells with PD-1.

FGL1/LAG3 is an immunosuppressive pathway independent of PD-1/PD-L1

A series of immunological animal experiments have confirmed the synergistic effect of the inhibitory receptors LAG3 and PD-1 on T cells. However, the FGL1/LAG3 pathway also plays an immunosuppressive role independent of the PD-1/PD-L1 pathway. It is well known that the PD-1/PD-L1 inhibitory pathway produces exhausted T cells (Fig. 4a). Anti-PD-1/PD-L1 antibodies can block this immune brake and release the antitumor activity of T cells (Fig. 4b). However, due to the existence of another inhibitory receptor, LAG3, on the T cell surface, another newly characterized immune checkpoint is generated when LAG3 interacts with its ligand FGL1 (Fig. 4c). It has been reported that blocking LAG-3 is more significant in T cell activation, proliferation and IFN-γ secretion than blocking the PD-1 pathway. Under tolerance conditions, signal transduction through the PD-1/PD-L1 and FGL1/LAG-3 pathways have different functional consequences for CD8+ T cell subsets; that is, external signaling initiation can affect the tolerance of CD8+ T cell subsets through the LAG3 and PD-1 pathways. The most direct manifestation upstream of these consequences is the production of three CD8+ T cell subsets with inconsistent expression and localization of LAG3 and PD-1. Further cytolytic functional analysis showed that the T cell subsets with high expression of LAG3 produced higher levels of cytokines, especially IFN-γ, TNF-α and CD107, than those with high expression of PD-1 but were not associated with the expression of the costimulatory molecules inducible T cell co-stimulator (ICOS) and 4-1BB (CD137). The differences in cytokine production patterns mentioned above indicate the independence of the two pathways. In addition, in animal experiments, more than 30% of MC38 tumor-bearing mice were found to have no tumor formation within 150 days of treatment with anti-FGL1/LAG3 as a monotherapy or in combination with anti-PD-1/PD-L1 therapy. Because of the high affinity between FGL1 and LAG3, FGL1/LAG3 and PD-1/PD-L1 can regulate T cells independently, and blocking both these checkpoints can produce synergistic antitumor effects. However, the upregulation of LAG-3 expression in NSCLC is associated with insensitivity to PD-1 axis blockade and a poor prognosis, which suggests the independence of immune escape pathways and the potential of the synergistic action of anti-PD-1 and anti-LAG3 antibodies in clinical trials.

Anti-FGL1 may overcome immune checkpoint blockade resistance via a tumor-intrinsic mechanism

Based on the above evidence that the FGL1/LAG3 pathway plays an important role in immune evasion during cancer development, anti-FGL1 may help overcome cancer immunotherapeutic resistance as a promising novel checkpoint. Characteristics that are necessary for the immune checkpoint inhibitor (ICI) response include IFN-γ signaling, antigen-presenting signaling, immune-evasive oncogenic signaling, and a mutational signaling landscape. It is well known that the T cell receptor (TCR) on the tumor-reactive T cell surface recognizes tumor neoantigens and subsequently releases IFN-γ, which binds to the IFN-γ receptor (IFN-γR1/R2) on the tumor cell surface, activates downstream JAK-STAT signaling pathways and further initiates PD-L1 transcription in tumor cells. The plasma level of IFN-γ was reported to be obviously increased after the injection of CD8+OT-1T cells together with the FGL1 antibody 177R4 into syngeneic mice (Table 3), which further proves that the blockade of FGL1 by a monoclonal antibody stimulates T cell immunity in a manner similar to anti-LAG3 therapy. Moreover, FGL1 is highly secreted from tumor cells, and higher plasma levels of FGL1 are associated with resistance to ICIs and poor prognosis in cancer patients. Hence, using FGL1 agents can theoretically enhance the antitumor effect of T cells and thus affect the acquired resistance of ICIs in patients with differential levels of PD-L1 expression.

Furthermore, antigen presentation blockade is another intrinsic factor underlying ICI resistance, which is mainly caused by MHC deficiency and loss of tumor antigenicity. MHC II is the first identified ligand of LAG3. However, their binding does not affect antitumor activity, suggesting that MHC II is not solely responsible for the function of LAG3. More valuable ligands presumably restart the “immune brake” by binding with LAG3. Therefore, as a newly discovered high-affinity ligand of LAG3, FGL1 has the potential to induce ICI resistance in a receptor-ligand interdependent manner. Moreover, cancers with a high tumor mutation burden (TMB) and high neoantigen expression, such as melanoma and NSCLC, are generally more sensitive to immune checkpoint blockade. However, these patients were observed to have higher plasma levels of FGL1 expression after the acquisition of ICI resistance. Thus, the FGL1 secretion level in plasma is a potential biomarker for identifying patients who will not benefit from ICI treatment. Finally, Wnt/β-catenin is an essential signaling pathway in cancer development. Emerging evidence indicates that the Wnt5α-β-catenin-PPARγ signaling pathway drives a metabolic program that triggers dendritic cell (DC) tolerance and immunotherapy resistance. PPARγ is the ultimate target of FGL1-induced lipid synthesis in adipocytes, suggesting that FGL1 has the potential to induce immunosuppression by regulating PPARγ synthesis in metabolic programs.

Anti-FGL1 may overcome immune checkpoint blockade resistance via exogenous factors

In addition to intrinsic factors, alterations in the functions and numbers of immune effector cells (mainly CD8+ T cells) in the tumor microenvironment (TME) are challenging for immunotherapies. Various immune cells (DCs, Tregs, myeloid-derived suppressor cells (MDSCs)) and their related secretory products and metabolites in the TME play essential roles in tumor development, metastasis and immunotherapeutic response. Persistent antigen exposure in the TME clearly results in sustained LAG3 expression, thereby having a substantial effect on the immunosuppression status and cytokine production. As a major LAG3 functional ligand independent of MHC-II, FGL1 is positively correlated with MDSC and Treg populations and negatively correlated with CD8+ T cells as determined by analysis of the TIMER database (http://timer.cistrome.org/). The regulatory effect of FGL1 on the TME was further demonstrated in a breast cancer model constructed using biomimetic nanomaterials designed to deliver a short interfering RNA targeting FGL1. Moreover, FGL1 was shown to be closely associated with tumor cell invasion and metastasis via acquisition of the EMT phenotype, which was underlined by bidirectional crosstalk between tumor cells and the surrounding TME. This evidence indicates preferential suppression of T cell immunity in the TME upon FGL1-LAG3 signaling. Indeed, the current insights into the mechanism by which FGL1 induces immunotherapy resistance via immunosuppression of the TME are relatively limited, and more in-depth investigations are still needed (Fig. 5).

Potential toxicity patterns of anti-FGL1 therapy

Based on clinical trials and medical practices, ICI therapies not only initiate the activation of an anticancer immune response but also cause a wide range of immune-related adverse events (irAEs), and the costs of immunotherapies continue to increase due to the diversity of T cell expansion and cell infiltration. Different from the toxic effects of traditional chemotherapy, the most frequently affected organs are the skin, digestive system (gastrointestinal, liver) and endocrine system, with symptoms of nausea, diarrhea, pruritus, rashes and thyroid problems, and fatal irAEs include myocarditis, pneumonia, hepatitis and meningitis. The frequency of irAEs and potential toxicity patterns are dependent on the immunotherapy strategy, exposure time, medicinal dose administered and individual intrinsic risk factors of the patient.

Some novel emerging immune checkpoints are approved for clinical trials in combination with CTLA-4 or PD-1(L1) blockade, such as anti-LAG-3, which increases the probability and new descriptions of irAEs (Table 4). Multiple new agents have been identified as targeting LAG3 across various tumors. The most common agent-related AEs, fatigue and nausea, are well tolerated. Nonetheless, the discovery of more novel checkpoints is still urgently needed in the paradigm of cancer treatment. Among the potential candidates, FGL1 has promise despite that it remains in the preclinical stage, and researchers are awaiting more advanced data. Theoretically, as another ligand of LAG3 in addition to the canonical ligand MHC-II, FGL1 may have more advantages than anti-LAG3 in regards to irAEs. Future studies should also optimize the selection of new ICIs by screening potential predictive biomarkers for the irAE risks.

Future directions of anti-FGL1 in cancer therapy

Despite the early stage of tumor research, FGL1 is a new immune checkpoint molecule that is thought to have a promising future in clinical applications, especially in NSCLC immunotherapy, which is attributed to its overexpression in NSCLC cells and close correlations with immune regulation, tumor neovascularization, EMT progression, resistance and metastasis. The novel discovery of a high-affinity interaction between FGL1 and LAG3 in immunology marks a major breakthrough in research on immune checkpoint blockade therapy. This strategy holds great potential as a third-generation immune checkpoint blockade after targeting CTLA-4 and PD-1/PD-L1. Currently, multiple clinical trials evaluating the synergistic effects of anti-LAG3 and anti-PD-1 antibodies are ongoing, and significant efficacy has been achieved in completed trials on melanoma (stage III/IV), metastatic breast cancer and RCC (stage IV). Although the number of ongoing clinical trials targeting FGL1 are not sufficient, a significant positive correlation between FGL1 expression and long-term prognosis has been observed for patients with multiple types of metastatic cancer who are treated with anti-PD-1/PD-L1 therapy (Table 2). Based on the above results, patients with advanced-stage tumors reliant on ICIs are likely to benefit from anti-FGL1 therapy. More prospective clinical trials targeting FGL1 alone or in combination with other ICI agents are needed to facilitate translocation from bench to bedside.

Conclusions

As an acute inflammatory factor secreted by the liver, FGL1 is upregulated in various solid tumors and associated with the EMT, proliferation, apoptosis and drug resistance of tumors as well as with poor prognosis. Most importantly, an immunosuppressive pathway distinct from that of PD-1/PD-L1 forms between FGL1 and the inhibitory receptor LAG3. Targeting FGL1 acts on both tumor cells themselves and immune cells, which exerts a two-way synergistic effect on advanced cancers through a targeted therapeutic strategy. Therefore, FGL1 demonstrates significant advantages as a biomarker for predicting the efficacy of anti-PD-1/PD-L1 therapy in patients with advanced tumors, and targeting FGL1 has promise as another promising immune checkpoint blockade strategy in clinical trials. Novel therapeutic strategies targeting FGL1 should be further explored in the treatment of cancer.

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    Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. 2018;378:158-68.

    Not in our library10.1056/nejmra1703481

  23. 23.

    Khan Z, Hammer C, Guardino E, Chandler GS, Albert ML. Mechanisms of immune-related adverse events associated with immune checkpoint blockade: using germline genetics to develop a personalized approach. Genome Med. 2019;11:39.

    Not in our library10.1186/s13073-019-0652-8

  24. 24.

    Li Y, Kang X, Wang H, Guo X, Zhou J, Duan L, et al. Clinical diagnosis and treatment of immune checkpoint inhibitor-associated adverse events in the digestive system. Thorac Cancer. 2020;11:829-834.

    Not in our library10.1111/1759-7714.13338

  25. 25.

    Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563-567.

    Not in our library10.1038/nature14011

  26. 26.

    Andrews LP, Marciscano AE, Drake CG, Vignali DA. LAG3 (CD223) as a cancer immunotherapy target. Immunol Rev. 2017;276:80-96.

    Not in our library10.1111/imr.12519

  27. 27.

    Shergold AL, Millar R, Nibbs RJB. Understanding and overcoming the resistance of cancer to PD-1/PD-L1 blockade. Pharmacol Res. 2019;145:104258.

    Not in our library10.1016/j.phrs.2019.104258

  28. 28.

    Jerby-Arnon L, Shah P, Cuoco MS, Rodman C, Su MJ, Melms JC, et al. A Cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell. 2018;175:984–97.

    Not in our library10.1016/j.cell.2018.09.006

  29. 29.

    Chen L, Diao L, Yang Y, Yi X, Rodriguez BL, Li Y, et al. CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1/PD-L1 blockade. Cancer Discov. 2018;8:1156-1175.

    Not in our library10.1158/2159-8290.cd-17-1033

  30. 30.

    Dosset M, Vargas TR, Lagrange A, Boidot R, Vegran F, Roussey A, et al. PD-1/PD-L1 pathway: an adaptive immune resistance mechanism to immunogenic chemotherapy in colorectal cancer. Oncoimmunology. 2018;7:e1433981.

    Not in our library10.1080/2162402x.2018.1433981

  31. 31.

    Nowicki TS, Hu-Lieskovan S, Ribas A. Mechanisms of resistance to PD-1 and PD-L1 blockade. Cancer J. 2018;24:47-53.

    Not in our library10.1097/ppo.0000000000000303

  32. 32.

    Wang Q, Wu X. Primary and acquired resistance to PD-1/PD-L1 blockade in cancer treatment. Int Immunopharmacol. 2017;46:210-219.

    Not in our library10.1016/j.intimp.2017.03.015

  33. 33.

    Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168:707-723.

    Not in our library10.1016/j.cell.2017.01.017

  34. 34.

    Shin DS, Zaretsky JM, Escuin-Ordinas H, Garcia-Diaz A, Hu-Lieskovan S, Kalbasi A, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 2017;7:188-201.

    Not in our library10.1158/2159-8290.cd-16-1223

  35. 35.

    Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568-571.

    Not in our library10.1038/nature13954

  36. 36.

    Mittal D, Vijayan D, Smyth MJ. Overcoming acquired PD-1/PD-L1 resistance with CD38 blockade. Cancer Discov. 2018;8:1066-1068.

    Not in our library10.1158/2159-8290.cd-18-0798

  37. 37.
    Mechanisms of resistance to immune checkpoint inhibitors · 2018
    No notice
  38. 38.

    Masucci GV, Cesano A, Eggermont A, Fox BA, Wang E, Marincola FM, et al. The need for a network to establish and validate predictive biomarkers in cancer immunotherapy. J Transl Med. 2017;15:223.

    Not in our library10.1186/s12967-017-1325-2

  39. 39.
    Resistance to PD-1/PD-L1 blockade cancer immunotherapy: mechanisms, predictive factors, and future perspectives · 2020
    No notice
  40. 40.

    Mintz MA, Felce JH, Chou MY, Mayya V, Xu Y, Shui JW, et al. The HVEM-BTLA axis restrains T cell help to germinal center B cells and functions as a cell-extrinsic suppressor in lymphomagenesis. Immunity. 2019;51:310–23.

    Not in our library10.1016/j.immuni.2019.05.022

  41. 41.
    Next generation of immune checkpoint therapy in cancer: new developments and challenges · 2018
    No notice
  42. 42.

    Ruffo E, Wu RC, Bruno TC, Workman CJ, Vignali DAA. Lymphocyte-activation gene 3 (LAG3): the next immune checkpoint receptor. Semin Immunol. 2019;42:101305.

    Not in our library10.1016/j.smim.2019.101305

  43. 43.

    Maruhashi T, Sugiura D, Okazaki IM, Okazaki T. LAG-3: from molecular functions to clinical applications. J Immunother Cancer. 2020;8.

    Not in our library10.1136/jitc-2020-001014

  44. 44.

    Lino AC, Dang VD, Lampropoulou V, Welle A, Joedicke J, Pohar J, et al. LAG-3 inhibitory receptor expression identifies immunosuppressive natural regulatory plasma cells. Immunity. 2018;49:120–33 e9.

    Not in our library10.1016/j.immuni.2018.06.007

  45. 45.
    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
  46. 46.

    Ohaegbulam KC, Assal A, Lazar-Molnar E, Yao Y, Zang X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med. 2015;21:24-33.

    Not in our library10.1016/j.molmed.2014.10.009

  47. 47.

    Marty Pyke R, Thompson WK, Salem RM, Font-Burgada J, Zanetti M, Carter H. Evolutionary pressure against MHC class II binding cancer mutations. Cell. 2018;175:416–28 e13.

    Not in our library10.1016/j.cell.2018.08.048

  48. 48.

    Johnson AM, Bullock BL, Neuwelt AJ, Poczobutt JM, Kaspar RE, Li HY, et al. Cancer cell-intrinsic expression of MHC class II regulates the immune microenvironment and response to anti-PD-1 therapy in lung adenocarcinoma. J Immunol. 2020;204:2295-2307.

    Not in our library10.4049/jimmunol.1900778

  49. 49.

    Newlaczyl AU, Yu LG. Galectin-3–a jack-of-all-trades in cancer. Cancer Lett. 2011;313:123-128.

    Not in our library10.1016/j.canlet.2011.09.003

  50. 50.

    Wang J, Sanmamed MF, Datar I, Su TT, Ji L, Sun J, et al. Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell. 2019;176:334–47.

    Not in our library10.1016/j.cell.2018.11.010

  51. 51.

    Yan J, Yu Y, Wang N, Chang Y, Ying H, Liu W, et al. LFIRE-1/HFREP-1, a liver-specific gene, is frequently downregulated and has growth suppressor activity in hepatocellular carcinoma. Oncogene. 2004;23:1939-1949.

    Not in our library10.1038/sj.onc.1207306

  52. 52.

    Wu HT, Ou HY, Hung HC, Su YC, Lu FH, Wu JS, et al. A novel hepatokine, HFREP1, plays a crucial role in the development of insulin resistance and type 2 diabetes. Diabetologia. 2016;59:1732-1742.

    Not in our library10.1007/s00125-016-3991-7

  53. 53.

    Calvaruso V. Hepassocin as a treatment for fulminant hepatic failure: will it translate from rats to human? Gut. 2010;59:709-710.

    Not in our library10.1136/gut.2009.201020

  54. 54.
    Targeted deletion of fibrinogen like protein 1 reveals a novel role in energy substrate utilization. · 2013
    Not checked
  55. 55.

    Gao M, Yan H, Yin RH, Wang Q, Zhan YQ, Yu M, et al. Hepassocin is required for hepatic outgrowth during zebrafish hepatogenesis. Biochem Biophys Res Commun. 2015;463:466-471.

    Not in our library10.1016/j.bbrc.2015.05.121

  56. 56.

    Wu HT, Chen SC, Fan KC, Kuo CH, Lin SY, Wang SH, et al. Targeting fibrinogen-like protein 1 is a novel therapeutic strategy to combat obesity. FASEB J. 2020;34:2958-2967.

    Not in our library10.1096/fj.201901925r

  57. 57.

    Watanabe T, Bertoletti A, Tanoto TA. PD-1/PD-L1 pathway and T-cell exhaustion in chronic hepatitis virus infection. J Viral Hepat. 2010;17:453-458.

    Not in our library10.1111/j.1365-2893.2009.01172.x

  58. 58.

    Xia L, Liu Y, Wang Y. PD-1/PD-L1 blockade therapy in advanced non-small-cell lung cancer: current status and future directions. Oncologist. 2019;24:S31-S41.

    Not in our library10.1634/theoncologist.2019-io-s1-s05

  59. 59.
    Anti-PD-1/PD-L1 Therapy for Non-Small-Cell Lung Cancer: Toward Personalized Medicine and Combination Strategies · 2018
    No notice
  60. 60.

    Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-128.

    Not in our library10.1126/science.aaa1348

  61. 61.

    Qu J, Jiang M, Wang L, Zhao D, Qin K, Wang Y, et al. Mechanism and potential predictive biomarkers of immune checkpoint inhibitors in NSCLC. Biomed Pharmacother. 2020;127:109996.

    Not in our library10.1016/j.biopha.2020.109996

  62. 62.

    Zhang X, Wang Y, Fan J, Chen W, Luan J, Mei X, et al. Blocking CD47 efficiently potentiated therapeutic effects of anti-angiogenic therapy in non-small cell lung cancer. J Immunother Cancer. 2019;7:346.

    Not in our library10.1186/s40425-019-0812-9

  63. 63.

    Allen E, Jabouille A, Rivera LB, Lodewijckx I, Missiaen R, Steri V, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med. 2017;9.

    Not in our library10.1126/scitranslmed.aak9679

  64. 64.

    Saarenheimo J, Eigeliene N, Andersen H, Tiirola M, Jekunen A. The value of liquid biopsies for guiding therapy decisions in non-small cell lung cancer. Front Oncol. 2019;9:129.

    Not in our library10.3389/fonc.2019.00129

  65. 65.

    Kloten L, Krahn S. Circulating tumor cell PD-L1 expression as biomarker for therapeutic efficacy of immune checkpoint inhibition in NSCLC. Cells. 2019;8.

    Not in our library10.3390/cells8080809

  66. 66.

    Chan KY, Lai PB, Squire JA, Beheshti B, Wong NL, Sy SM, et al. Positional expression profiling indicates candidate genes in deletion hotspots of hepatocellular carcinoma. Mod Pathol. 2006;19:1546-1554.

    Not in our library10.1038/modpathol.3800674

  67. 67.

    Nayeb-Hashemi H, Desai A, Demchev V, Bronson RT, Hornick JL, Cohen DE, et al. Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development. Biochem Biophys Res Commun. 2015;465:167-173.

    Not in our library10.1016/j.bbrc.2015.07.078

  68. 68.

    Jung TW, Chung YH, Kim HC, Abd El-Aty AM, Jeong JH. Hyperlipidemia-induced hepassocin in the liver contributes to insulin resistance in skeletal muscle. Mol Cell Endocrinol. 2018;470:26-33.

    Not in our library10.1016/j.mce.2017.10.014

  69. 69.

    Ou HY, Wu HT, Lin CH, Du YF, Hu CY, Hung HC, et al. The hepatic protection effects of hepassocin in hyperglycemic crisis. J Clin Endocrinol Metab. 2017;102:2407-2415.

    Not in our library10.1210/jc.2016-3287

  70. 70.

    Liu Z, Ukomadu C. Fibrinogen-like protein 1, a hepatocyte derived protein is an acute phase reactant. Biochem Biophys Res Commun. 2008;365:729-734.

    Not in our library10.1016/j.bbrc.2007.11.069

  71. 71.

    Han NK, Jung MG, Jeong YJ, Son Y, Han SC, Park S, et al. Plasma fibrinogen-like 1 as a potential biomarker for radiation-induced liver injury. Cells. 2019;8.

    Not in our library10.3390/cells8091042

  72. 72.
    mRNA and lncRNA Expression Profiling of Radiation-Induced Gastric Injury Reveals Potential Radiation-Responsive Transcription Factors · 2019
    Not checked
  73. 73.

    Jin H, Kang G-Y, Jeon S, Kim J-M, Park YN, Cho J, et al. Identification of molecular signatures involved in radiation-induced lung fibrosis. J Mol Med. 2018;97:37-47.

    Not in our library10.1007/s00109-018-1715-9

  74. 74.

    Leu JI, Crissey MA, Leu JP, Ciliberto G, Taub R. Interleukin-6-induced STAT3 and AP-1 amplify hepatocyte nuclear factor 1-mediated transactivation of hepatic genes, an adaptive response to liver injury. Mol Cell Biol. 2001;21:414-424.

    Not in our library10.1128/mcb.21.2.414-424.2001

  75. 75.

    Batlle E, Massague J. Transforming growth factor-beta signaling in immunity and cancer. Immunity. 2019;50:924-940.

    Not in our library10.1016/j.immuni.2019.03.024

  76. 76.

    Murakami M, Kamimura D, Hirano T. Pleiotropy and specificity: insights from the interleukin 6 family of cytokines. Immunity. 2019;50:812-831.

    Not in our library10.1016/j.immuni.2019.03.027

  77. 77.

    Schmidt-Arras D, Rose-John S. IL-6 pathway in the liver: from physiopathology to therapy. J Hepatol. 2016;64:1403-1415.

    Not in our library10.1016/j.jhep.2016.02.004

  78. 78.

    Yu HT, Yu M, Li CY, Zhan YQ, Xu WX, Li YH, et al. Specific expression and regulation of hepassocin in the liver and down-regulation of the correlation of HNF1alpha with decreased levels of hepassocin in human hepatocellular carcinoma. J Biol Chem. 2009;284:13335-13347.

    Not in our library10.1074/jbc.m806393200

  79. 79.
    Targeting STAT3 in Cancer Immunotherapy · 2020
    No notice
  80. 80.

    Thilakasiri PS, Dmello RS, Nero TL, Parker MW, Ernst M, Chand AL. Repurposing of drugs as STAT3 inhibitors for cancer therapy. Semin Cancer Biol. 2021;68:31-46.

    Not in our library10.1016/j.semcancer.2019.09.022

  81. 81.

    Furtek SL, Backos DS, Matheson CJ, Reigan P. Strategies and approaches of targeting STAT3 for cancer treatment. ACS Chem Biol. 2016;11:308-318.

    Not in our library10.1021/acschembio.5b00945

  82. 82.

    Marzec M, Zhang Q, Goradia A, Raghunath PN, Liu X, Paessler M, et al. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7–H1). Proc Natl Acad Sci U S A. 2008;105:20852-20857.

    Not in our library10.1073/pnas.0810958105

  83. 83.

    Wang J, Wei W, Tang Q, Lu L, Luo Z, Li W, et al. Oxysophocarpine suppresses hepatocellular carcinoma growth and sensitizes the therapeutic blockade of anti-Lag-3 via reducing FGL1 expression. Cancer Med. 2020;9:7125-7136.

    Not in our library10.1002/cam4.3151

  84. 84.

    Liu S, Guo Y, Lu L, Lu J, Ke M, Xu T, et al. Fibrinogen-like protein 1 is a novel biomarker for predicting disease activity and prognosis of rheumatoid arthritis. Front Immunol. 2020;11:579228.

    Not in our library10.3389/fimmu.2020.579228

  85. 85.

    Han L, Ao X, Lin S, Guan S, Zheng L, Han X, et al. Quantitative comparative proteomics reveal biomarkers for dengue disease severity. Front Microbiol. 2019;10:2836.

    Not in our library10.3389/fmicb.2019.02836

  86. 86.
    CRISPR/Cas9 -mediated gene knockout of Anopheles gambiae FREP1 suppresses malaria parasite infection · 2018
    No notice
  87. 87.

    Yu J, Li J, Shen J, Du F, Wu X, Li M, et al. The role of Fibrinogen-like proteins in cancer. Int J Biol Sci. 2021;17:1079-1087.

    Not in our library10.7150/ijbs.56748

  88. 88.

    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674.

    Not in our library10.1016/j.cell.2011.02.013

  89. 89.

    Su J, Morgani SM, David CJ, Wang Q, Er EE, Huang YH, et al. TGF-beta orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1. Nature. 2020;577:566-571.

    Not in our library10.1038/s41586-019-1897-5

  90. 90.

    Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 2009;19:156-172.

    Not in our library10.1038/cr.2009.5

  91. 91.

    Li H, Batth IS, Qu X, Xu L, Song N, Wang R, et al. IGF-IR signaling in epithelial to mesenchymal transition and targeting IGF-IR therapy: overview and new insights. Mol Cancer. 2017;16:6.

    Not in our library10.1186/s12943-016-0576-5

  92. 92.
    A gene regulatory network to control EMT programs in development and disease · 2019
    No notice
  93. 93.

    Bie F, Wang G, Qu X, Wang Y, Huang C, Wang Y, et al. Loss of FGL1 induces epithelialmesenchymal transition and angiogenesis in LKB1 mutant lung adenocarcinoma. Int J Oncol. 2019;55:697-707.

    Not in our library10.3892/ijo.2019.4838

  94. 94.

    Zhang Y, Qiao HX, Zhou YT, Hong L, Chen JH. Fibrinogenlikeprotein 1 promotes the invasion and metastasis of gastric cancer and is associated with poor prognosis. Mol Med Rep. 2018;18:1465-1472.

    Not in our library10.3892/mmr.2018.9097

  95. 95.

    Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 2008;68:3645-3654.

    Not in our library10.1158/0008-5472.can-07-2938

  96. 96.

    van Roy F, Berx G. The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci. 2008;65:3756-3788.

    Not in our library10.1007/s00018-008-8281-1

  97. 97.

    Morrow CS, Porter TJ, Xu N, Arndt ZP, Ako-Asare K, Heo HJ, et al. Vimentin coordinates protein turnover at the aggresome during neural stem cell quiescence exit. Cell Stem Cell. 2020;26:558–68 e9.

    Not in our library10.1016/j.stem.2020.01.018

  98. 98.

    Nakamura-Ishizu A, Suda T. Dynamic changes in the Niche with N-cadherin revisited: the HSC "Niche Herein". Cell Stem Cell. 2019;24:355-356.

    Not in our library10.1016/j.stem.2019.02.007

  99. 99.

    Richardson AM, Havel LS, Koyen AE, Konen JM, Shupe J, Wiles WG, et al. Vimentin is required for lung adenocarcinoma metastasis via heterotypic tumor cell-cancer-associated fibroblast interactions during collective invasion. Clin Cancer Res. 2018;24:420–32.

    Not in our library10.1158/1078-0432.ccr-17-1776

  100. 100.

    Serres MP, Samwer M, Truong Quang BA, Lavoie G, Perera U, Gorlich D, et al. F-Actin interactome reveals vimentin as a key regulator of actin organization and cell mechanics in mitosis. Dev Cell. 2020;52:210–22.

    Not in our library10.1016/j.devcel.2019.12.011

  101. 101.

    Su Y, Li J, Shi C, Hruban RH, Radice GL. N-cadherin functions as a growth suppressor in a model of K-ras-induced PanIN. Oncogene. 2016;35:3335-3341.

    Not in our library10.1038/onc.2015.382

  102. 102.
    RNA m6A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail · 2019
    Retracted
  103. 103.

    Kim MS, Lee HS, Kim YJ, Lee DY, Kang SG, Jin W. MEST induces Twist-1-mediated EMT through STAT3 activation in breast cancers. Cell Death Differ. 2019;26:2594-2606.

    Not in our library10.1038/s41418-019-0322-9

  104. 104.
    Fibronectin in Cancer: Friend or Foe · 2019
    No notice
  105. 105.
    Matrix Metalloproteinase-12 Is Required for Granuloma Progression · 2020
    Not checked
  106. 106.

    Tsai HY, Fu SL, Tseng LM, Chiu JH, Lin CH. hnRNPK S379 phosphorylation participates in migration regulation of triple negative MDA-MB-231 cells. Sci Rep. 2019;9:7611.

    Not in our library10.1038/s41598-019-44063-z

  107. 107.

    Liu M, Yang J, Zhang Y, Zhou Z, Cui X, Zhang L, et al. ZIP4 promotes pancreatic cancer progression by repressing ZO-1 and claudin-1 through a ZEB1-dependent transcriptional mechanism. Clin Cancer Res. 2018;24:3186-3196.

    Not in our library10.1158/1078-0432.ccr-18-0263

  108. 108.

    Schwayer C, Shamipour S, Pranjic-Ferscha K, Schauer A, Balda M, Tada M, et al. Mechanosensation of tight junctions depends on ZO-1 phase separation and flow. Cell. 2019;179:937–52.

    Not in our library10.1016/j.cell.2019.10.006

  109. 109.
    Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation · 2017
    No notice
  110. 110.
    Targeting Epithelial–Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer · 2016
    No notice
  111. 111.

    Lazarova D, Bordonaro M. ZEB1 mediates drug resistance and EMT in p300-deficient CRC. J Cancer. 2017;8:1453-1459.

    Not in our library10.7150/jca.18762

  112. 112.

    Wu X, Wu Q, Zhou X, Huang J. SphK1 functions downstream of IGF-1 to modulate IGF-1-induced EMT, migration and paclitaxel resistance of A549 cells: a preliminary in vitro study. J Cancer. 2019;10:4264-4269.

    Not in our library10.7150/jca.32646

  113. 113.

    Qi LN, Xiang BD, Wu FX, Ye JZ, Zhong JH, Wang YY, et al. Circulating tumor cells undergoing EMT provide a metric for diagnosis and prognosis of patients with hepatocellular carcinoma. Cancer Res. 2018;78:4731-4744.

    Not in our library10.1158/0008-5472.can-17-2459

  114. 114.

    Sun C, Gao W, Liu J, Cheng H, Hao J. FGL1 regulates acquired resistance to Gefitinib by inhibiting apoptosis in non-small cell lung cancer. Respir Res. 2020;21:210.

    Not in our library10.1186/s12931-020-01477-y

  115. 115.

    Chiu CF, Hsu MI, Yeh HY, Park JM, Shen YS, Tung TH, et al. Eicosapentaenoic acid inhibits KRAS mutant pancreatic cancer cell growth by suppressing hepassocin expression and STAT3 phosphorylation. Biomolecules. 2021;11.

    Not in our library10.3390/biom11030370

  116. 116.

    Son Y, Shin NR, Kim SH, Park SC, Lee HJ. Fibrinogen-like protein 1 modulates sorafenib resistance in human hepatocellular carcinoma cells. Int J Mol Sci. 2021;22.

    Not in our library10.3390/ijms22105330

  117. 117.

    Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology. 2008;135:1972–83.

    Not in our library10.1053/j.gastro.2008.08.008

  118. 118.
    Combined targeting of AKT and mTOR synergistically inhibits proliferation of hepatocellular carcinoma cells · 2012
    Not checked
  119. 119.
    Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer · 2020
    No notice
  120. 120.

    Barbi J, Pardoll D, Pan F. Treg functional stability and its responsiveness to the microenvironment. Immunol Rev. 2014;259:115-139.

    Not in our library10.1111/imr.12172

  121. 121.

    Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity. 2012;37:785-799.

    Not in our library10.1016/j.immuni.2012.09.010

  122. 122.
    Transcriptional and epigenetic basis of Treg cell development and function: its genetic anomalies or variations in autoimmune diseases · 2020
    No notice
  123. 123.

    Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211:781-790.

    Not in our library10.1084/jem.20131916

  124. 124.

    Alfaro C, Teijeira A, Onate C, Perez G, Sanmamed MF, Andueza MP, et al. Tumor-produced interleukin-8 attracts human myeloid-derived suppressor cells and elicits extrusion of neutrophil extracellular traps (NETs). Clin Cancer Res. 2016;22:3924-3936.

    Not in our library10.1158/1078-0432.ccr-15-2463

  125. 125.

    Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017;5:3-8.

    Not in our library10.1158/2326-6066.cir-16-0297

  126. 126.

    Lu X, Horner JW, Paul E, Shang X, Troncoso P, Deng P, et al. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature. 2017;543:728-732.

    Not in our library10.1038/nature21676

  127. 127.

    Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol. 2018;19:108-119.

    Not in our library10.1038/s41590-017-0022-x

  128. 128.

    Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, et al. Blockade of B7–H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med. 2003;9:562-567.

    Not in our library10.1038/nm863

  129. 129.

    Kim YJ, Won CH, Lee MW, Choi JH, Chang SE, Lee WJ. Correlation between tumor-associated macrophage and immune checkpoint molecule expression and its prognostic significance in cutaneous melanoma. J Clin Med. 2020;9.

    Not in our library10.3390/jcm9082500

  130. 130.
    Harnessing tumor-associated macrophages as aids for cancer immunotherapy · 2019
    No notice
  131. 131.

    Singhal S, Stadanlick J, Annunziata MJ, Rao AS, Bhojnagarwala PS, O'Brien S, et al. Human tumor-associated monocytes/macrophages and their regulation of T cell responses in early-stage lung cancer. Sci Transl Med. 2019;11.

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    Hopkins RA, Connolly JE. The specialized roles of immature and mature dendritic cells in antigen cross-presentation. Immunol Res. 2012;53:91-107.

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    Yin W, Ouyang S, Li Y, Xiao B, Yang H. Immature dendritic cell-derived exosomes: a promise subcellular vaccine for autoimmunity. Inflammation. 2012;36:232-240.

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    Das M, Zhu C, Kuchroo VK. Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev. 2017;276:97-111.

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    Ngiow SF, von Scheidt B, Akiba H, Yagita H, Teng MW, Smyth MJ. Anti-TIM3 antibody promotes T cell IFN-gamma-mediated antitumor immunity and suppresses established tumors. Cancer Res. 2011;71:3540-3551.

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    Wolf Y, Anderson AC, Kuchroo VK. TIM3 comes of age as an inhibitory receptor. Nat Rev Immunol. 2020;20:173-185.

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    Blake SJ, Dougall WC, Miles JJ, Teng MW, Smyth MJ. Molecular pathways: targeting CD96 and TIGIT for cancer immunotherapy. Clin Cancer Res. 2016;22:5183-5188.

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    Chauvin JM, Zarour HM. TIGIT in cancer immunotherapy. J Immunother Cancer. 2020;8.

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    Nowak EC, Lines JL, Varn FS, Deng J, Sarde A, Mabaera R, et al. Immunoregulatory functions of VISTA. Immunol Rev. 2017;276:66-79.

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    Duraiswamy J, Freeman GJ, Coukos G. Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. Cancer Res. 2013;73:6900-6912.

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    Terawaki S, Chikuma S, Shibayama S, Hayashi T, Yoshida T, Okazaki T, et al. IFN-alpha directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. J Immunol. 2011;186:2772-2779.

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    Wu C, Zhu Y, Jiang J, Zhao J, Zhang XG, Xu N. Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem. 2006;108:19-24.

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    Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations · 2018
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    Zhang J, Dang F, Ren J, Wei W. Biochemical aspects of PD-L1 regulation in cancer immunotherapy. Trends Biochem Sci. 2018;43:1014-1032.

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    Schalper KA, Carvajal-Hausdorf D, McLaughlin J, Altan M, Velcheti V, Gaule P, et al. Differential expression and significance of PD-L1, IDO-1, and B7–H4 in human lung cancer. Clin Cancer Res. 2017;23:370-378.

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    Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, et al. Role of LAG-3 in regulatory T cells. Immunity. 2004;21:503-513.

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    Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali DA. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J Immunol. 2004;172:5450-5455.

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    Nagasaki J, Togashi Y, Sugawara T, Itami M, Yamauchi N, Yuda J, et al. The critical role of CD4+ T cells in PD-1 blockade against MHC-II–expressing tumors such as classic Hodgkin lymphoma. Blood Adv. 2020;4:4069-4082.

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    Hemon P, Jean-Louis F, Ramgolam K, Brignone C, Viguier M, Bachelez H, et al. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J Immunol. 2011;186:5173-5183.

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    Casati C, Camisaschi C, Novellino L, Mazzocchi A, Triebel F, Rivoltini L, et al. Human lymphocyte activation gene-3 molecules expressed by activated T cells deliver costimulation signal for dendritic cell activation. J Immunol. 2008;180:3782-3788.

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    Atkinson V, Khattak A, Haydon A, Eastgate M, Roy A, Prithviraj P, et al. Eftilagimod alpha, a soluble lymphocyte activation gene-3 (LAG-3) protein plus pembrolizumab in patients with metastatic melanoma. J Immunother Cancer. 2020;8.

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    He Y, Wang Y, Zhao S, Zhao C, Zhou C, Hirsch FR. sLAG-3 in non-small-cell lung cancer patients' serum. Onco Targets Ther. 2018;11:4781-4784.

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    Targeting LAG-3 and PD-1 to Enhance T Cell Activation by Antigen-Presenting Cells · 2018
    No notice
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    Niu B, Zhou F, Su Y, Wang L, Xu Y, Yi Z, et al. Different expression characteristics of LAG3 and PD-1 in sepsis and their synergistic effect on T cell exhaustion: a new strategy for immune checkpoint blockade. Front Immunol. 2019;10:1888.

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    Okazaki T, Okazaki IM, Wang J, Sugiura D, Nakaki F, Yoshida T, et al. PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice. J Exp Med. 2011;208:395-407.

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    He Y, Yu H, Rozeboom L, Rivard CJ, Ellison K, Dziadziuszko R, et al. LAG-3 protein expression in non-small cell lung cancer and its relationship with PD-1/PD-L1 and tumor-infiltrating lymphocytes. J Thorac Oncol. 2017;12:814-823.

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    Rouhani SJ, Eccles JD, Riccardi P, Peske JD, Tewalt EF, Cohen JN, et al. Roles of lymphatic endothelial cells expressing peripheral tissue antigens in CD4 T-cell tolerance induction. Nat Commun. 2015;6:6771.

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    Zelba H, Bedke J, Hennenlotter J, Mostbock S, Zettl M, Zichner T, et al. PD-1 and LAG-3 dominate checkpoint receptor-mediated T-cell inhibition in renal cell carcinoma. Cancer Immunol Res. 2019;7:1891-1899.

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    Sun L, Zhang L, Yu J, Zhou Y, Shi C, Wasan HS, et al. To be or not to be: whether anti-angiogenic agent combined with immune checkpoint inhibitoris necessary in the treatment of advanced or metastatic renal cell carcinoma. Med Oncol. 2020;37:15.

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  162. 162.

    Wang Y, Dong T, Xuan Q, Zhao H, Qin L, Zhang Q. Lymphocyte-activation gene-3 expression and prognostic value in neoadjuvant-treated triple-negative breast cancer. J Breast Cancer. 2018;21:124-133.

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    Du H, Yi Z, Wang L, Li Z, Niu B, Ren G. The co-expression characteristics of LAG3 and PD-1 on the T cells of patients with breast cancer reveal a new therapeutic strategy. Int Immunopharmacol. 2020;78:106113.

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    Grosso JF, Goldberg MV, Getnet D, Bruno TC, Yen HR, Pyle KJ, et al. Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J Immunol. 2009;182:6659-6669.

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  165. 165.
    Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using multiplex quantitative analysis · 2020
    No notice
  166. 166.

    Zhang L, Zhang X, Liu Y, Zhang T, Wang Z, Gu M, et al. PD-L1(+) aneuploid circulating tumor endothelial cells (CTECs) exhibit resistance to the checkpoint blockade immunotherapy in advanced NSCLC patients. Cancer Lett. 2020;469:355-366.

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    Sanmamed MF, Etxeberria I, Otano I, Melero I. Twists and turns to translating 4–1BB cancer immunotherapy. Sci Transl Med. 2019;11.

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  168. 168.
    ICOS Co-Stimulation: Friend or Foe? · 2016
    No notice
  169. 169.

    Xiao Z, Mayer AT, Nobashi TW, Gambhir SS. ICOS is an indicator of T-cell-mediated response to cancer immunotherapy. Cancer Res. 2020;80:3023-3032.

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    Datar I, Sanmamed MF, Wang J, Henick BS, Choi J, Badri T, et al. Expression analysis and significance of PD-1, LAG-3, and TIM-3 in human non-small cell lung cancer using spatially resolved and multiparametric single-cell analysis. Clin Cancer Res. 2019;25:4663-4673.

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    Kalbasi A, Ribas A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol. 2020;20:25-39.

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    Pitt JM, Vetizou M, Daillere R, Roberti MP, Yamazaki T, Routy B, et al. Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and -extrinsic factors. Immunity. 2016;44:1255-1269.

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    Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375:819-829.

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    Gao J, Shi LZ, Zhao H, Chen J, Xiong L, He Q, et al. Loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell. 2016;167:397–404.

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    Rodig SJ, Gusenleitner D, Jackson DG, Gjini E, Giobbie-Hurder A, Jin C, et al. MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. Sci Transl Med. 2018;10.

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    Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution · 2017
    No notice
  177. 177.

    Andreae S, Buisson S, Triebel F. MHC class II signal transduction in human dendritic cells induced by a natural ligand, the LAG-3 protein (CD223). Blood. 2003;102:2130-2137.

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    Liu C, Zheng S, Jin R, Wang X, Wang F, Zang R, et al. The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicity. Cancer Lett. 2020;470:95-105.

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    Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature. 2015;523:231-235.

    Not in our library10.1038/nature14404

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    Grasso CS, Giannakis M, Wells DK, Hamada T, Mu XJ, Quist M, et al. Genetic mechanisms of immune evasion in colorectal cancer. Cancer Discov. 2018;8:730-749.

    Not in our library10.1158/2159-8290.cd-17-1327

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    Holtzhausen A, Zhao F, Evans KS, Tsutsui M, Orabona C, Tyler DS, et al. Melanoma-derived Wnt5a promotes local dendritic-cell expression of IDO and immunotolerance: opportunities for pharmacologic enhancement of immunotherapy. Cancer Immunol Res. 2015;3:1082-1095.

    Not in our library10.1158/2326-6066.cir-14-0167

  182. 182.

    Zhao F, Xiao C, Evans KS, Theivanthiran T, DeVito N, Holtzhausen A, et al. Paracrine Wnt5a-beta-catenin signaling triggers a metabolic program that drives dendritic cell tolerization. Immunity. 2018;48:147–60 e7.

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    Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science. 2015;348:74-80.

    Not in our library10.1126/science.aaa6204

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    Kim K, Skora AD, Li Z, Liu Q, Tam AJ, Blosser RL, et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci USA. 2014;111:11774-11779.

    Not in our library10.1073/pnas.1410626111

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    Gong C, Yu X, Zhang W, Han L, Wang R, Wang Y, et al. Regulating the immunosuppressive tumor microenvironment to enhance breast cancer immunotherapy using pH-responsive hybrid membrane-coated nanoparticles. J Nanobiotechnology. 2021;19:58.

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    Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019;16:563-580.

    Not in our library10.1038/s41571-019-0218-0

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    Boutros C, Tarhini A, Routier E, Lambotte O, Ladurie FL, Carbonnel F, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13:473-486.

    Not in our library10.1038/nrclinonc.2016.58

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    Burova E, Hermann A, Dai J, Ullman E, Halasz G, Potocky T, et al. Preclinical development of the anti-LAG-3 antibody REGN3767: characterization and activity in combination with the anti-PD-1 antibody cemiplimab in human PD-1xLAG-3-Knockin mice. Mol Cancer Ther. 2019;18:2051-2062.

    Not in our library10.1158/1535-7163.mct-18-1376

  189. 189.

    Lee JB, Ha SJ, Kim HR. Clinical insights into novel immune checkpoint inhibitors. Front Pharmacol. 2021;12:681320.

    Not in our library10.3389/fphar.2021.681320

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    Rossi G, Russo A, Tagliamento M, Tuzi A, Nigro O, Vallome G, et al. Precision medicine for NSCLC in the era of immunotherapy: new biomarkers to select the most suitable treatment or the most suitable patient. Cancers (Basel). 2020;12.

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    Brody R, Zhang Y, Ballas M, Siddiqui MK, Gupta P, Barker C, et al. PD-L1 expression in advanced NSCLC: insights into risk stratification and treatment selection from a systematic literature review. Lung Cancer. 2017;112:200-215.

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    Ramjiawan RR, Griffioen AW, Duda DG. Anti-angiogenesis for cancer revisited: is there a role for combinations with immunotherapy? Angiogenesis. 2017;20:185-204.

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  193. 193.

    Tabchi S, Blais N. Antiangiogenesis for advanced non-small-cell lung cancer in the era of immunotherapy and personalized medicine. Front Oncol. 2017;7:52.

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    Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014;26:605-622.

    Not in our library10.1016/j.ccell.2014.10.006

  195. 195.

    Larsen JE, Nathan V, Osborne JK, Farrow RK, Deb D, Sullivan JP, et al. ZEB1 drives epithelial-to-mesenchymal transition in lung cancer. J Clin Invest. 2016;126:3219-3235.

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    Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15:232-239.

    Not in our library10.1016/j.ccr.2009.01.021

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    Manegold C, Dingemans AC, Gray JE, Nakagawa K, Nicolson M, Peters S, et al. The potential of combined immunotherapy and antiangiogenesis for the synergistic treatment of advanced NSCLC. J Thorac Oncol. 2017;12:194-207.

    Not in our library10.1016/j.jtho.2016.10.003

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    Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131:58-67.

    Not in our library10.1182/blood-2017-06-741033

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