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Soluble PD-1 and PD-L1: predictive and prognostic significance in cancer

Xinxin Zhu, Jinghe Lang

Oncotarget · 2017 · Review

doi:10.18632/oncotarget.18311

Abstract

// Xinxin Zhu 1 and Jinghe Lang 1 1 Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China Correspondence to: Jinghe Lang, email: langjh@hotmail.com , doctorlangjh@163.com Keywords: soluble, PD-1, PD-L1, tumor immunity, biomarker Received: April 25, 2017 Accepted: May 22, 2017 Published: May 31, 2017 ABSTRACT The membrane-bound molecules programmed death 1 (PD-1) and its ligand PD-L1 (PD-1/PD-L1) belong to the immune checkpoint pathway. PD-1 pathway downregulates effector T cells in immune response, thereby causing immune suppression. Recent studies have revealed that membrane-bound PD-1 and PD-L1 also have soluble forms. These soluble forms increase the complexity and diversity of the composition and function of the PD-1/PD-L1 signaling pathway. However, the exact roles of these molecules remain unknown. The objective of this systematic review was to elucidate the biological significance of soluble PD-1/PD-L1 in human cancers and evaluate whether they are potential diagnostic, therapeutic, or prognostic biomarkers. We expect to provide new clues for future research on soluble PD-1/PD-L1 pathway in human malignant tumors.

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

Malignant tumor cells use various methods of immune suppression to resist antitumor immunity. One of these methods is modifying the PD-1/PD-L1 pathway, which is called the “immune checkpoint”. The PD-1/PD-L1 pathway not only controls excessive immune activation normally, but also appears to be a means through which tumors evade the immune system. The activation of this pathway can lead to tumor immune escape and promote tumor cell growth including the following aspects: T cell tolerance, T cell apoptosis, T cell exhaustion, enhancing immunosuppressive Treg cell function, inducible co-stimulatory molecule and PD-1 disbalance. Therefore, immunotherapeutic agents that can improve the immune response or reduce immunosuppression are essential for treating human cancers. The current immunotherapies for malignant tumors include therapeutic vaccines, adoptive T cell transfer, immune modulators, cytokines, and immune checkpoint inhibitors. The PD-1/PD-L1 immune checkpoint represents an available and promising pathway that can be blocked to reverse tumor-mediated immunosuppression.

PD-1 is mainly expressed on different immune cells and has two ligands, namely PD-L1 (B7-H1 or CD274) and PD-L2 (B7-DC or CD273). Although the interaction of PD-1/PD-L2 shows a 2–6-fold higher affinity compared with the interaction of PD-1/PD-L1, PD-L1 is regarded as the primary ligand of PD-1. Recently, the soluble forms of PD-1 and PD-L1 (sPD-1 and sPD-L1) have been detected in the blood of patients with tumors. However, the roles of sPD-1 and sPD-L1 have not been fully elucidated. This systematic review discusses the production of sPD-1/PD-L1 and evaluates the physiological and pathological significance of their levels in human blood.

Structure and production of mPD-1 and mPD-L1

T-cell immune responses are vital in adaptive antitumor immune responses through the direct killing of target tumor cells or indirect inhibition by cytokines. The PD-1/PD-L1 pathway molecules including membrane-bound forms of PD-1/PD-L1 (mPD-1/PD-L1) and sPD-1/PD-L1 play immunosuppressive roles in tumor-driven T-cell immune responses. To date, an increasing number of studies have demonstrated that the anti-mPD-1/PD-L1 monoclonal antibodies (mAbs) can reverse the immunosuppression and might serve as a promising clinical strategy for controlling human malignancies. We will first discuss the production and expression of the classic mPD-1/PD-L1 because the fundamental knowledge of mPD-1/PD-L1 facilitates the understanding of the PD-1/PD-L1 pathway and the roles of sPD-1/PD-L1.

Structure and production of mPD-1

The PD-1 gene was discovered in 1992 as an upregulated gene in a T-cell hybridoma and hematopoietic progenitor cell line. The components of mPD-1, a 288-amino acid (aa, ∼55 kDa) type I transmembrane glycoprotein, include an immunoglobulin (Ig) superfamily domain, stalk of approximately 20 aa, transmembrane domain, and an intracellular domain of approximately 95 aa residues. The intracellular domain contains an immunoreceptor tyrosine-based switch motif (ITSM) and an immunoreceptor tyrosine-based inhibitory motif (ITIM). ITSMs are essential for the delivery of inhibitory signals. The aa sequence of PD-1 near the C-terminal tyrosine is highly conserved between humans and mice and is related to the Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2. On the contrary, the N-terminal tyrosine is not associated with either SHP-1 or SHP-2.

PD-1 is expressed on active T cells, B cells, natural killer T cells, and myeloid cells such as dendritic cells (DCs), and activated monocytes. PD-1 expression can be induced following T-cell receptor (TCR)-mediated activation and stimulation by cytokines such as interleukin (IL)-2, IL-7, IL-15, and IL-21. The mPD-1 glycoprotein is a coinhibitory molecule, which belongs to the CD28 family. The expression of mPD-1 protein in a wide variety T lymphocytes is contrary to the limited expression of other CD28 family members, thereby implying that mPD-1 suppresses a wider range of immune responses than do other inhibitory members of the CD28 family. The role of PD-1 in the promotion of immunity evasion and development and progression of several types of malignancies, including non–small-cell lung cancer (NSCLC), melanomas, breast cancer, renal cell carcinomas (RCCs), and Hodgkin diseasehas been confirmed.

Structure and production of mPD-L1

The two ligands of PD-1 are the B7 family molecules, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273). PD-L1 is a 290-aa type I transmembrane glycoprotein that consists of IgC- and IgV-like extracellular domains, signal sequence, transmembrane domain, and intracellular domains.

The expression profile of PD-L1 is considerably more promiscuous than that of PD-1. Cells of the hematopoietic lineage, including active T cells, B cells, NK cells, DCs, monocytes, and macrophages, can express mPD-L1. It is also expressed on activated vascular endothelial cells, cultured bone marrow–derived mast cells and mesenchymal stem cells. Furthermore, in humans, mPD-L1 is extensively expressed in the tonsils, placental syncytiotrophoblasts, and lungs, where it mediates human immune tolerance and human malignancies of the kidney, ovary, pancreas, stomach, esophagus, and liver. PD-L1 mRNA or mPD-L1 protein can be upregulated by cytokines, such as IFN-γ, IL-4, IL-10, VEGF, hypoxia-inducible factor-1α, and the constitutive oncogene pathways, including IFN-γ/JAK2/IFN, PI3K, and MEK/ERK/STAT1. The expression levels of mPD-L1 on tumor cells tend to be associated, to some extent, with cancer progression and are predictive biomarkers of tumorigenesis, unfavorable outcomes, and improved response to treatment with PD-1/PD-L1 blockades in gastric, breast, renal, and ovarian cancers.

Mechanism of PD-1/PD-L1 signaling

The inhibitory signaling of the PD-1 pathway was initially analyzed in the B cell line, IIA1.6, by using a chimeric molecule consisting of a PD-1 cytoplasmic region and an IgG Fc receptor type IIB extracellular region (FcPD). In the IIA1.6 cell line, co-crosslinking of B cell receptors (BCRs) and FcPD induced the phosphorylation of tyrosine residues in both ITSM and ITIM. Only the phosphorylated tyrosine residue in ITSM recruits SHP-2 through its SH2 domain and later phosphorylates the SHP-2 molecule. Subsequently, phosphorylated SHP-2 dephosphorylates the proximal well-known signal transducers of BCR, such as Ig α/β and Syk, which cause the deactivation of downstream molecules, including PLCγ2, PI3K, and ERK. Finally, the deactivated signal transducers lead to the suppression of acute-phase responses such as Ca2+ mobilization as well as long-term effects such as cell growth retardation. In summary, these results indicate that PD-1 suppresses BCR signals by recruiting the SHP-2 molecule to its phosphotyrosine and dephosphorylating vital signal transducers of BCR signaling (Figure 1).

In T cells, the PD-1 pathway attenuates TCR signals through similar mechanisms. PD-1 downregulates the effector phase of T-cell immune responses by elevating the threshold of T-cell activation, inhibiting T-cell proliferation, and promoting activated T-cell apoptosis. The mechanism of PD-1 signaling is associated with dephosphorylation of molecules belonging to the TCR pathway and the transmission of suppressive signals. PD-1 ligation, along with TCR signaling leads to the phosphorylation of the cytoplasmic region tyrosine, followed by the recruitment of SHP-2 to C-terminal tyrosine in the ITSM. Thereafter, SHP-2 dephosphorylates TCR-related zeta-chain-associated protein kinase 70 (ZAP70) and the CD28-related PI3K pathway, thereby causing inhibition of downstream signaling (Figure 1). Moreover, blockade or inhibition of PI3K signaling activation and the subsequent cell survival gene Bcl-XL reduce IL-2 production and glucose metabolism. The downregulation of IL-2 further induces the anergy in CD4+ T and CD8+ T cells. Notably, phosphorylated ITSM recruits SHP-1 in addition to SHP-2, whereas the contribution of SHP-1 to the suppressive function of PD-1 is considerably less than that of SHP-2.

Production of sPD-1 and sPD-L1

Numerous costimulatory molecules in immunoregulation pathways assume two forms of expression, namely the membrane-bound and soluble forms. The soluble form of molecules is usually generated by proteolytic cleavage of the membrane-bound form of the costimulatory proteins, as in the case of soluble tumor necrosis factor and sB7-H3, or by translation of alternative spliced mRNA, as in the case of sB7–2 and sCTLA-4. Similarly, the presence of soluble forms of PD-1/PD-L1 has been confirmed. Increasing evidence suggests that the blood levels of sPD-1/PD-L1 might facilitate the prediction of clinicopathological characteristics, treatment response, and survival outcomes in patients with cancer.

Production of sPD-1

Five splice variants of PD-1 mRNA transcripts have been cloned from human peripheral blood mononuclear cells: flPD-1, PD-1 Deltaex2, PD-1 Deltaex3, PD-1 Deltaex2,3, and PD-1 Deltaex2,3,4 (Figure 2). The flPD-1 transcript demonstrated complete homology with the mPD-1 sequence. PD-1 Deltaex2 and PD-1 Deltaex3 are generated by alternative splicing where exon 2 and 3 (extracellular IgV-like domain and transmembrane domain, respectively) are spliced out. PD-1 Deltaex2,3 lacks exon 2 and 3. PD-1 Deltaex2,3,4 lacks exon 2, 3, and 4 (intracellular domain) and includes a premature stop codon in exon 5. PD-1 Deltaex2, PD-1 Deltaex2,3, and PD-1 Deltaex2,3,4 cannot bind to their ligands because of the lack of exon 2. The PD-1 Deltaex3 variant encodes the sPD-1, which is not detectable in healthy individuals.

Production of sPD-L1

The sPD-L1, is detectable in supernatants from mPD-L1+ cell lines rather than in those from mPD-L1− cell lines, thereby indicating that mPD-L1 that is expressed on the cell surface might be a source of sPD-L1. However, other sources of sPD-L1 cannot be excluded. Researchers have found that both immune and tumor cells can be sources of sPD-L1. Among the immune cells, activated T cells and myeloid cells exhibit an increased level of mPD-L1, but the release of sPD-L1 is a feature of myeloid-derived cells. This suggests that a regulatory mechanism that is different from that of mPD-L1 may control the production of sPD-L1. Moreover, no association was discovered between tumor PD-L1 expression (immunohistochemical analysis) and sPD-L1 levels (enzyme-linked immunosorbent assay analysis) in patients with diffuse large B-cell lymphomas (DLBCLs) and renal cell carcinomas, which indicated that the tumor microenvironment, including nonmalignant cells, may also generate sPD-L1.

Furthermore, sPD-L1 was expressed in normal human serum and the levels of sPD-L1 in human serum increased with age. Children aged 3–10 years had the lowest expression levels of sPD-L1, whereas adults aged 51–70 years had the highest levels (0.725 ± 0.181 ng/mL vs 1.040 ± 0.681 ng/mL, respectively). Moreover, the sPD-L1 levels might increase when matrix metalloproteinases (MMPs) cleave the extracellular fraction of mPD-L1; therefore, the production of sPD-L1 is suppressed by MMP inhibitors. However, whether the cleavage occurs randomly or is controlled by unique mechanisms remains to be determined.

Functions of sPD-1 and sPD-L1

Tumor-related mPD-1 and mPD-L1 contribute to tumor immune escape. Immunotherapeutic strategies against malignant tumors using their antagonists have aroused researchers’ intense interest. The sPD-1/PD-L1 may represent unanticipated elements that contribute to immune response as well.

Functions of sPD-1

Several studies on the functions of sPD-1 are based on animal models. In a study on murine hepatocarcinoma, the eukaryotic expression plasmid encoded sPD-1 protein was constructed, and its significant improvement in the antitumor immunity was proven. Later, researchers used the adeno-associated virus to deliver sPD-1 into tumor sites, which inhibited H22 hepatoma cell growth, enhanced lysis of cancer cells and finally prolonged the overall survival (OS) of tumor-bearing mice.

As aforementioned, the importance of the PD-1 checkpoint pathway in T-cell anergy and immunosuppression has been confirmed. In this regard, antibody-based checkpoint blockades to reverse T-cell function in cancer immunotherapies have a promising future. Several PD-1/PD-L1 pathway blocking monoclonal antibodies (mAb), such as nivolumab, pembrolizumab, pidilizumab, durvalumab, and atezolizumab, have either entered into clinical trials or have been approved for clinical treatment and have shown potent therapeutic efficacies in multiple advanced-stage tumors. Studies have hypothesized that binding of sPD-1 to mPD-L1/mPD-L2 may prevent mPD-1 from combining with PD-L1 and PD-L2, thereby counteracting mPD-1-mediated inhibitory effects on T cells. On one hand, the PD-1/mPD-L1 combination could provide direct inhibitory signal for T cells in the immune response. On the other hand, a great deal of sPD-L1 could afford distant influence to the activated T cells by the intervention of PD-1/mPD-L1 interactions. Moreover, sPD-1 may be more effective and potent than anti-PD-1 mAb for the following reasons: first, sPD-1 can suppress all three combinations (PD-L1:PD-1, PD-L2:PD-1, and PD-L1:B7-1(CD80)) that inhibit T-cell immune responses (Figure 3). Second, unlike mAb immunotherapy, the sustained but lower level of serum sPD-1 may reduce side effects while still exerting a relatively strong therapeutic effect. Third, sPD-1 is more cost effective than mAb as the latter necessitates high and frequent doses.

In addition, the use of sPD-1 combined with other agents produced promising outcomes in vitro experiments. Blockade of tumor PD-1 pathway by hydrodynamic injection of plasmid DNA encoding sPD-1 and tumor-derived heat shock protein-70 (HSP70) peptide complexes reduced pulmonary metastasis of B16F1 melanoma cells and therefore increased the OS rate in female C57BL/6 mice. Similarly, the in vitro coadministration of human papilloma virus-16 E7 DNA vaccine with sPD-1 DNA considerably improved E7-specific CD8+ T-cell responses, leading to valid antitumor effects against E7-expressing tumors. The codelivery of sPD-1 DNA increased the maturation of DCs, which was accompanied by upregulation of DC maturation markers such as major histocompatibility complex II (MHC II). Considering that DC maturation is mediated by activated T lymphocytes, we speculate that DC maturation upregulated by sPD-1 might be influenced by the augmentation of T-cell responses. All these findings indicate that the sPD-1 plays an adjuvant role in enhancing antigen-specific T-cell immunity responses.

A few clinical studies have analyzed the relationship between the level of sPD-1 in blood and clinicopathological characteristics in patients with cancer for evaluating the predictive role of sPD-1 (Table 1). In patients with NSCLC, a study investigated the change in concentration of sPD-1 in the blood at initiation of erlotinib treatment and at the time of clinical resistance to erlotinib. It reported that patients with increased sPD-1 levels during erlotinib treatment were associated with prolonged progression-free survival (p = 0.013) and OS (p = 0.006). By contrast, in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), Cheng et al. assessed the effect of sPD-1 levels on the long-term dynamics of HBV load and HCC risk. They found that the longitudinal effects of increased sPD-1 level maintained higher viral loads for 4 years or more, and plasma quartile sPD-1 levels were positively related to HCC risk in men. Additional studies are needed to explore the potential and precise mechanisms underlying the discovered association between sPD-1 and malignant tumors.

Functions of sPD-L1

In contrast to sPD-1, a higher number of studies has been conducted on the mechanisms and functions of sPD-L1 in humans than in animal models (Table 1). At present, whether sPD-L1 can bind to PD-1, similarly to mPD-L1, and deliver an inhibitory signal is debatable. Wan et al. showed that the levels of sPD-1 and sPD-L1 were considerably higher in the serum and synovial fluid samples of patients with rheumatoid arthritis compared with controls. In vitro experiments, CD4+ T lymphocytes were cocultured with synovial fluid mononuclear cells. The addition of PD-1 or PD-L1 fusion proteins at a concentration range higher than 20 ng/mL led to a significantly increased level of T-cell proliferation which can express mPD-1 or mPD-L1. This finding suggested that the properties of mPD-1 and mPD-L1 are upregulated by their soluble forms.

On the basis of the predictive role of sPD-L1, Zheng et al. designed a study to evaluate the correlation between sPD-L1 level and the prognosis of patients with advanced gastric cancer. They discovered that the higher level of sPD-L1 was correlated with differentiated cancer and the absence of lymph node metastasis (p = 0.026 and p = 0.041, respectively). Moreover, in this study, the adenocarcinoma patients with higher levels of sPD-L1 had better prognosis than did low-level patients (p = 0.028). However, on the contrary, other studies have revealed that the sPD-L1 levels may indicate a poor prognosis or treatment resistance. Frigola et al. discovered that the exposure of CD4+ and CD8+ T lymphocytes to either tumor cell-derived sPD-L1 or mature DCs-derived sPD-L1 induced apoptosis. Similarly, Zhang et al. reported that the average levels of sPD-L1 in patients with advanced NSCLC and healthy controls were significantly different (0.723±0.081 vs 0.565±0.048 ng/mL, respectively, p < 0.001). In addition, the median OS in the low- and high-level groups were 26.8 (95% CI: 26.2∼27.4 months) and 18.7 months (95% CI: 15.9∼21.5 months), respectively. This suggested that patients with a low sPD-L1 levels may have a longer survival time. A French multicenter clinical trial revealed that patients with elevated sPD-L1 experienced a poorer prognosis (p < 0.001) than did the controls, and the sPD-L1 level returned to its normal value after complete remission of DLBCL. Therefore, sPD-L1 may be a potent predicting biomarker in DLBCL, which indicates the utility of alternative therapeutic strategies. Several other studies have also confirmed that sPD-L1 is a negative therapeutic and prognostic biomarker in malignant tumors, such as multiple myeloma and renal cell carcinoma. However, to date, the reasons of sPD-L1for the dichotomous effects on T lymphocytes remain unknown.

CONCLUSIONS

In recent years, with the growth of economies and improvement in living standards, cancer incidence and mortality have increase significantly. Cancer is the leading cause of death in China and is a major public health problem. The detection and evaluation of cancer through mass screening and by using less invasive and more efficient markers are major public health requirements. Mass screening biomarkers, such as alpha-fetoprotein, antigen, carbohydrate antigen (CA) 19–9 and CA125, prostate-specific antigen, and lactate dehydrogenase, are generally used in clinical practice; however, they do not accurately or completely predict diagnosis, disease development, immunotherapeutic sensitivity, and prognosis. Accumulated data indicates that sPD-1 and sPD-L1, which can be easily detected in clinical practice, may play significant roles in tumor pathogenesis, immune responses, and prediction. Therefore, sPD-1/PD-L1 may provide new biomarkers and insight into potential treatment strategies including immunotherapy in malignant tumor.

In addition, the treatment strategies targeting PD-1/PD-L1 with mAbs such as nivolumab, pembrolizumab, and atezolizumab and so on exhibited promising results and fundamentally changed cancer treatments. However, apart from the dichotomous effect of sPD-L1, the PD-1 pathway is complex and the molecular mechanisms remain unclear. Whether the PD-1 pathway mAbs can upregulate the antitumor responses of sPD-1/PD-L1 need further study. Moreover, the synergistic therapeutic effects of sPD-1 in combination with other antitumor agents, such as HSP70 peptide vaccine and IL-21, provide a new direction for future antitumor strategies.

The PD-1 pathway has generated immense academic and commercial interest in the fight against cancer. The application of sPD-1 and sPD-L1 in the treatment of tumors is defined to date, but their initial results appear promising. We speculate that with the growing number of successful clinical trials associated with PD-1 pathway mAbs, additional investigations and studies on sPD-1 and sPD-L1 in cancers will soon be conducted.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

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    Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793-800.

    Not in our library10.1038/nm730

  34. 34.

    Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, Sengupta S, Frank I, Parker AS, Zincke H, Blute ML, Sebo TJ, Cheville JC, Kwon ED. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res. 2006;66:3381-85.

    Not in our library10.1158/0008-5472.can-05-4303

  35. 35.

    Abiko K, Matsumura N, Hamanishi J, Horikawa N, Murakami R, Yamaguchi K, Yoshioka Y, Baba T, Konishi I, Mandai M. IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br J Cancer. 2015;112:1501-09.

    Not in our library10.1038/bjc.2015.101

  36. 36.

    Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, Nakamura S, Enomoto K, Yagita H, Azuma M, Nakajima Y. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13:2151-57.

    Not in our library10.1158/1078-0432.ccr-06-2746

  37. 37.

    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.

    Not in our library10.1016/j.acthis.2006.01.003

  38. 38.

    Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, Mizuno T, Yoriki R, Kashizuka H, Yane K, Tsushima F, Otsuki N, Yagita H, et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res. 2005;11:2947-53.

    Not in our library10.1158/1078-0432.ccr-04-1469

  39. 39.

    Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, Zhou J, Li BZ, Shi YH, Xiao YS, Xu Y, Fan J. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009;15:971-79.

    Not in our library10.1158/1078-0432.ccr-08-1608

  40. 40.
    PD-1 and its ligands are important immune checkpoints in cancer · 2016
    No notice
  41. 41.

    Ota K, Azuma K, Kawahara A, Hattori S, Iwama E, Tanizaki J, Harada T, Matsumoto K, Takayama K, Takamori S, Kage M, Hoshino T, Nakanishi Y, Okamoto I. Induction of PD-L1 Expression by the EML4-ALK Oncoprotein and Downstream Signaling Pathways in Non-Small Cell Lung Cancer. Clin Cancer Res. 2015;21:4014-21.

    Not in our library10.1158/1078-0432.ccr-15-0016

  42. 42.

    Qing Y, Li Q, Ren T, Xia W, Peng Y, Liu GL, Luo H, Yang YX, Dai XY, Zhou SF, Wang D. Upregulation of PD-L1 and APE1 is associated with tumorigenesis and poor prognosis of gastric cancer. Drug Des Devel Ther. 2015;9:901-09.

    Not in our library10.2147/dddt.s75152

  43. 43.
    High PD-L1 expression was associated with poor prognosis in 870 Chinese patients with breast cancer · 2015
    No notice
  44. 44.

    Shin SJ, Jeon YK, Cho YM, Lee JL, Chung DH, Park JY, Go H. The Association Between PD-L1 Expression and the Clinical Outcomes to Vascular Endothelial Growth Factor-Targeted Therapy in Patients With Metastatic Clear Cell Renal Cell Carcinoma. Oncologist. 2015;20:1253-60.

    Not in our library10.1634/theoncologist.2015-0151

  45. 45.

    Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA. 2001;98:13866-71.

    Not in our library10.1073/pnas.231486598

  46. 46.

    Chikuma S, Terawaki S, Hayashi T, Nabeshima R, Yoshida T, Shibayama S, Okazaki T, Honjo T. PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo. J Immunol. 2009;182:6682-89.

    Not in our library10.4049/jimmunol.0900080

  47. 47.

    Bishop KD, Harris JE, Mordes JP, Greiner DL, Rossini AA, Czech MP, Phillips NE. Depletion of the programmed death-1 receptor completely reverses established clonal anergy in CD4(+) T lymphocytes via an interleukin-2-dependent mechanism. Cell Immunol. 2009;256:86-91.

    Not in our library10.1016/j.cellimm.2009.01.008

  48. 48.

    Jin HT, Ahmed R, Okazaki T. Role of PD-1 in regulating T-cell immunity. Curr Top Microbiol Immunol. 2011;350:17-37.

    Not in our library10.1007/82_2010_116

  49. 49.

    Hikita A, Tanaka N, Yamane S, Ikeda Y, Furukawa H, Tohma S, Suzuki R, Tanaka S, Mitomi H, Fukui N. Involvement of a disintegrin and metalloproteinase 10 and 17 in shedding of tumor necrosis factor-alpha. Biochem Cell Biol. 2009;87:581-93.

    Not in our library10.1139/o09-015

  50. 50.

    Zhang G, Hou J, Shi J, Yu G, Lu B, Zhang X. Soluble CD276 (B7-H3) is released from monocytes, dendritic cells and activated T cells and is detectable in normal human serum. Immunology. 2008;123:538-46.

    Not in our library10.1111/j.1365-2567.2007.02723.x

  51. 51.

    Jeannin P, Magistrelli G, Aubry JP, Caron G, Gauchat JF, Renno T, Herbault N, Goetsch L, Blaecke A, Dietrich PY, Bonnefoy JY, Delneste Y. Soluble CD86 is a costimulatory molecule for human T lymphocytes. Immunity. 2000;13:303-12.

    Not in our library10.1016/s1074-7613(00)00030-3

  52. 52.

    Oaks MK, Hallett KM. Cutting edge: a soluble form of CTLA-4 in patients with autoimmune thyroid disease. J Immunol. 2000;164:5015-18.

    Not in our library10.4049/jimmunol.164.10.5015

  53. 53.

    Sorensen SF, Demuth C, Weber B, Sorensen BS, Meldgaard P. Increase in soluble PD-1 is associated with prolonged survival in patients with advanced EGFR-mutated non-small cell lung cancer treated with erlotinib. Lung Cancer. 2016;100:77-84.

    Not in our library10.1016/j.lungcan.2016.08.001

  54. 54.
    Serum levels of soluble programmed death ligand 1 predict treatment response and progression free survival in multiple myeloma · 2015
    No notice
  55. 55.

    Nielsen C, Ohm-Laursen L, Barington T, Husby S, Lillevang ST. Alternative splice variants of the human PD-1 gene. Cell Immunol. 2005;235:109-16.

    Not in our library10.1016/j.cellimm.2005.07.007

  56. 56.

    Wan B, Nie H, Liu A, Feng G, He D, Xu R, Zhang Q, Dong C, Zhang JZ. Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis. J Immunol. 2006;177:8844-50.

    Not in our library10.4049/jimmunol.177.12.8844

  57. 57.

    Chen Y, Wang Q, Shi B, Xu P, Hu Z, Bai L, Zhang X. Development of a sandwich ELISA for evaluating soluble PD-L1 (CD274) in human sera of different ages as well as supernatants of PD-L1+ cell lines. Cytokine. 2011;56:231-38.

    Not in our library10.1016/j.cyto.2011.06.004

  58. 58.

    He XH, Xu LH, Liu Y. Identification of a novel splice variant of human PD-L1 mRNA encoding an isoform-lacking Igv-like domain. Acta Pharmacol Sin. 2005;26:462-68.

    Not in our library10.1111/j.1745-7254.2005.00086.x

  59. 59.

    Frigola X, Inman BA, Krco CJ, Liu X, Harrington SM, Bulur PA, Dietz AB, Dong H, Kwon ED. Soluble B7-H1: differences in production between dendritic cells and T cells. Immunol Lett. 2012;142:78-82.

    Not in our library10.1016/j.imlet.2011.11.001

  60. 60.

    Frigola X, Inman BA, Lohse CM, Krco CJ, Cheville JC, Thompson RH, Leibovich B, Blute ML, Dong H, Kwon ED. Identification of a soluble form of B7-H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma. Clin Cancer Res. 2011;17:1915-23.

    Not in our library10.1158/1078-0432.ccr-10-0250

  61. 61.

    Takahashi N, Iwasa S, Sasaki Y, Shoji H, Honma Y, Takashima A, Okita NT, Kato K, Hamaguchi T, Yamada Y. Serum levels of soluble programmed cell death ligand 1 as a prognostic factor on the first-line treatment of metastatic or recurrent gastric cancer. J Cancer Res Clin Oncol. 2016;142:1727-38.

    Not in our library10.1007/s00432-016-2184-6

  62. 62.

    Rossille D, Gressier M, Damotte D, Maucort-Boulch D, Pangault C, Semana G, Le Gouill S, Haioun C, Tarte K, Lamy T, Milpied N, Fest T, Damaj G, et al. Groupe Ouest-Est des Leucémies et Autres Maladies du Sang, and Groupe Ouest-Est des Leucémies et Autres Maladies du Sang. High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-Cell lymphoma: results from a French multicenter clinical trial. Leukemia. 2014;28:2367-75.

    Not in our library10.1038/leu.2014.137

  63. 63.

    Ruf M, Moch H, Schraml P. PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma. Int J Cancer. 2016;139:396-403.

    Not in our library10.1002/ijc.30077

  64. 64.

    Wang X, Ni S, Chen Q, Ma L, Jiao Z, Wang C, Jia G. Bladder cancer cells induce immunosuppression of T cells by supporting PD-L1 expression in tumour macrophages partially through interleukin 10. Cell Biol Int. 2017;41:177-86.

    Not in our library10.1002/cbin.10716

  65. 65.

    Lipson EJ, Forde PM, Hammers HJ, Emens LA, Taube JM, Topalian SL. Antagonists of PD-1 and PD-L1 in Cancer Treatment. Semin Oncol. 2015;42:587-600.

    Not in our library10.1053/j.seminoncol.2015.05.013

  66. 66.

    He L, Zhang G, He Y, Zhu H, Zhang H, Feng Z. Blockade of B7-H1 with sPD-1 improves immunity against murine hepatocarcinoma. Anticancer Res. 2005;25:3309-13.

    Not in our library

  67. 67.

    Elhag OA, Hu XJ, Wen-Ying Z, Li X, Yuan YZ, Deng LF, Liu DL, Liu YL, Hui G. Reconstructed adeno-associated virus with the extracellular domain of murine PD-1 induces antitumor immunity. Asian Pac J Cancer Prev. 2012;13:4031-36.

    Not in our library10.7314/apjcp.2012.13.8.4031

  68. 68.

    Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Contr. 2014;21:231-37.

    Not in our library10.1177/107327481402100308

  69. 69.

    Brahmer JR, Hammers H, Lipson EJ. Nivolumab: targeting PD-1 to bolster antitumor immunity. Future Oncol. 2015;11:1307-26.

    Not in our library10.2217/fon.15.52

  70. 70.

    Martin-Liberal J, Kordbacheh T, Larkin J. Safety of pembrolizumab for the treatment of melanoma. Expert Opin Drug Saf. 2015;14:957-64.

    Not in our library10.1517/14740338.2015.1021774

  71. 71.

    Bryan LJ, Gordon LI. Pidilizumab in the treatment of diffuse large B-cell lymphoma. Expert Opin Biol Ther. 2014;14:1361-68.

    Not in our library10.1517/14712598.2014.942637

  72. 72.

    Antonia S, Goldberg SB, Balmanoukian A, Chaft JE, Sanborn RE, Gupta A, Narwal R, Steele K, Gu Y, Karakunnel JJ, Rizvi NA. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016;17:299-308.

    Not in our library10.1016/s1470-2045(15)00544-6

  73. 73.

    Vansteenkiste J, Wauters E, Park K, Rittmeyer A, Sandler A, Spira A. Prospects and progress of atezolizumab in non-small cell lung cancer. Expert Opin Biol Ther. 2017;17:781-89.

    Not in our library10.1080/14712598.2017.1309389

  74. 74.

    Song MY, Park SH, Nam HJ, Choi DH, Sung YC. Enhancement of vaccine-induced primary and memory CD8(+) T-cell responses by soluble PD-1. J Immunother. 2011;34:297-306.

    Not in our library10.1097/cji.0b013e318210ed0e

  75. 75.

    Geng H, Zhang GM, Xiao H, Yuan Y, Li D, Zhang H, Qiu H, He YF, Feng ZH. HSP70 vaccine in combination with gene therapy with plasmid DNA encoding sPD-1 overcomes immune resistance and suppresses the progression of pulmonary metastatic melanoma. Int J Cancer. 2006;118:2657-64.

    Not in our library10.1002/ijc.21795

  76. 76.

    Cheng HY, Kang PJ, Chuang YH, Wang YH, Jan MC, Wu CF, Lin CL, Liu CJ, Liaw YF, Lin SM, Chen PJ, Lee SD, Yu MW. Circulating programmed death-1 as a marker for sustained high hepatitis B viral load and risk of hepatocellular carcinoma. PLoS One. 2014;9:e95870.

    Not in our library10.1371/journal.pone.0095870

  77. 77.

    Zhang P, Ouyang S, Wang J, Huang Z, Wang J, Liao L. [Levels of programmed death-1 and programmed death ligand-1 in the peripheral blood of patients with oral squamous cell carcinoma and its clinical implications]. Hua Xi Kou Qiang Yi Xue Za Zhi. 2015;33:529-33.

    Not in our library10.7518/hxkq.2015.05.019

  78. 78.

    Cheng S, Zheng J, Zhu J, Xie C, Zhang X, Han X, Song B, Ma Y, Liu J. PD-L1 gene polymorphism and high level of plasma soluble PD-L1 protein may be associated with non-small cell lung cancer. Int J Biol Markers. 2015;30:e364-68.

    Not in our library10.5301/jbm.5000170

  79. 79.

    Finkelmeier F, Canli Ö, Tal A, Pleli T, Trojan J, Schmidt M, Kronenberger B, Zeuzem S, Piiper A, Greten FR, Waidmann O. High levels of the soluble programmed death-ligand (sPD-L1) identify hepatocellular carcinoma patients with a poor prognosis. Eur J Cancer. 2016;59:152-59.

    Not in our library10.1016/j.ejca.2016.03.002

  80. 80.

    Huang SY, Lin HH, Lin CW, Li CC, Yao M, Tang JL, Hou HA, Tsay W, Chou SJ, Cheng CL, Tien HF. Soluble PD-L1: A biomarker to predict progression of autologous transplantation in patients with multiple myeloma. Oncotarget. 2016;7:62490-502.

    Not in our library10.18632/oncotarget.11519

  81. 81.

    Zheng Z, Bu Z, Liu X, Zhang L, Li Z, Wu A, Wu X, Cheng X, Xing X, Du H, Wang X, Hu Y, Ji J. Level of circulating PD-L1 expression in patients with advanced gastric cancer and its clinical implications. Chin J Cancer Res. 2014;26:104-11.

    Not in our library10.3978/j.issn.1000-9604.2014.02.08

  82. 82.

    Okuma Y, Hosomi Y, Nakahara Y, Watanabe K, Sagawa Y, Homma S. High plasma levels of soluble programmed cell death ligand 1 are prognostic for reduced survival in advanced lung cancer. Lung Cancer. 2017;104:1-6.

    Not in our library10.1016/j.lungcan.2016.11.023

  83. 83.

    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10-29.

    Not in our library10.3322/caac.20138

  84. 84.

    Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115-32.

    Not in our library10.3322/caac.21338

  85. 85.

    Wong RJ, Ahmed A, Gish RG. Elevated alpha-fetoprotein: differential diagnosis - hepatocellular carcinoma and other disorders. Clin Liver Dis. 2015;19:309-23.

    Not in our library10.1016/j.cld.2015.01.005

  86. 86.

    Grunnet M, Sorensen JB. Carcinoembryonic antigen (CEA) as tumor marker in lung cancer. Lung Cancer. 2012;76:138-43.

    Not in our library10.1016/j.lungcan.2011.11.012

  87. 87.

    Li Y, Li DJ, Chen J, Liu W, Li JW, Jiang P, Zhao X, Guo F, Li XW, Wang SG. Application of Joint Detection of AFP, CA19-9, CA125 and CEA in Identification and Diagnosis of Cholangiocarcinoma. Asian Pac J Cancer Prev. 2015;16:3451-55.

    Not in our library10.7314/apjcp.2015.16.8.3451

  88. 88.

    Vertosick EA, Poon BY, Vickers AJ. Relative value of race, family history and prostate specific antigen as indications for early initiation of prostate cancer screening. J Urol. 2014;192:724-28.

    Not in our library10.1016/j.juro.2014.03.032

  89. 89.

    Fiume L, Manerba M, Vettraino M, Di Stefano G. Inhibition of lactate dehydrogenase activity as an approach to cancer therapy. Future Med Chem. 2014;6:429-45.

    Not in our library10.4155/fmc.13.206

  90. 90.

    Tan S, Chen D, Liu K, He M, Song H, Shi Y, Liu J, Zhang CW, Qi J, Yan J, Gao S, Gao GF. Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies. Protein Cell. 2016;7:866-77.

    Not in our library10.1007/s13238-016-0337-7

  91. 91.

    Pan XC, Li L, Mao JJ, Yao W, Zheng JN, Liu M, Fu JJ. Synergistic effects of soluble PD-1 and IL-21 on antitumor immunity against H22 murine hepatocellular carcinoma. Oncol Lett. 2013;5:90-96.

    Not in our library10.3892/ol.2012.966

  92. 92.

    Zatloukalová P, Pjechová M, Babčanová S, Hupp TR, Vojtěšek B. [The Role of PD-1/PD-L1 Signaling Pathway in Antitumor Immune Response]. Klin Onkol. 2016;29(Suppl 4):72-77.

    Not in our library

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