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PD-L1 expression in human cancers and its association with clinical outcomes

Authors Wang X, Teng F, Kong L, Yu J

Received 5 February 2016

Accepted for publication 16 May 2016

Published 12 August 2016 Volume 2016:9 Pages 5023—5039

DOI https://doi.org/10.2147/OTT.S105862

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Geoffrey Pietersz

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Xin Wang,1,2,* Feifei Teng,2,3,* Li Kong,2 Jinming Yu2

1School of Medicine and Life Sciences, University of Jinan – Shandong Academy of Medical Sciences, 2Department of Radiation Oncology, Shandong Cancer Hospital and Institute, 3School of Medicine, Shandong University, Jinan, People’s Republic of China

*These authors contributed equally to this work

Abstract: PD-L1 is an immunoinhibitory molecule that suppresses the activation of T cells, leading to the progression of tumors. Overexpression of PD-L1 in cancers such as gastric cancer, hepatocellular carcinoma, renal cell carcinoma, esophageal cancer, pancreatic cancer, ovarian cancer, and bladder cancer is associated with poor clinical outcomes. In contrast, PD-L1 expression correlates with better clinical outcomes in breast cancer and merkel cell carcinoma. The prognostic value of PD-L1 expression in lung cancer, colorectal cancer, and melanoma is controversial. Blocking antibodies that target PD-1 and PD-L1 have achieved remarkable response rates in cancer patients who have PD-L1-overexpressing tumors. However, using PD-L1 as an exclusive predictive biomarker for cancer immunotherapy is questionable due to the low accuracy of PD-L1 immunohistochemistry staining. Factors that affect the accuracy of PD-L1 immunohistochemistry staining are as follows. First, antibodies used in different studies have different sensitivity. Second, in different studies, the cut-off value of PD-L1 staining positivity is different. Third, PD-L1 expression in tumors is not uniform, and sampling time and location may affect the results of PD-L1 staining. Therefore, better understanding of tumor microenvironment and use of other biomarkers such as gene marker and combined index are necessary to better identify patients who will benefit from PD-1/PD-L1 checkpoint blockade therapy.

Keywords: PD-L1, prognostic value, checkpoint blockade, immunotherapy, clinical outcome

 

Introduction

The classic T cell activation is regulated by two signal transduction pathways: one is antigen dependent, and the other is antigen independent. The antigen-independent signaling includes positive and negative second signals. PD-1 and CTLA-4 are two immune-inhibitory checkpoint molecules that suppress T cell-mediated immune responses, leading to the development of tumors.1 Cancer immunoediting is a process that consists of immunosurveillance and tumor progression.2 It has three phases: elimination, equilibrium, and escape. In elimination phase, tumor cells are recognized by upregulated tumor antigen expression and killed by different types of immune effector cells. In equilibrium phase, tumor cells change into variants and induce immunosuppression to avoid constant immune pressure, resulting in a state of functional dormancy of the tumor. In escape phase, various immunosuppressive molecules and cytokines are activated by the tumor cells and contribute to tumor outgrowth, causing clinically apparent disease. PD-L1 is a PD-1 ligand that plays an important role in the inhibition of T cell-mediated immune response. Binding of PD-L1 to PD-1 causes the exhaustion of effector T cells and immune escape of tumor cells, leading to poor prognosis. In rare cases, positive PD-L1 expression has been reported to be associated with better clinical outcome. Clinical trials have demonstrated that monoclonal antibodies (mAbs) that target PD-L1 or its receptor PD-1 prevent the inhibitory effects of PD-1/PD-L1 pathway and enhance T cell functions, leading to impressive outcomes in patients with melanoma, renal cell carcinoma (RCC), non-small-cell lung cancer (NSCLC), and bladder cancer.35 However, the predictive effects of PD-L1 in response to PD-1/PD-L1 antibodies in some tumors are not conclusive, and the indication of PD-L1 expression in tumors remains controversial and needs to be understood profoundly. This review focuses on PD-L1 expression and its association with clinical outcomes in different cancers and factors affecting the accuracy of prediction of PD-L1. We also discuss the value of PD-L1 in predicting the clinical efficacy of PD-1/PD-L1 checkpoint blockades in cancer patients.

Expression and biological function of PD-L1

PD-L1 is mainly expressed on the surface of tumor cells and antigen-presenting cells in various solid malignancies such as squamous cell carcinoma of the head and neck, melanoma, and carcinomas of the brain, thyroid, thymus, esophagus, lung, breast, gastrointestinal tract, colorectum, liver, pancreas, kidney, adrenal cortex, bladder, urothelium, ovary, and skin.612 In tumor microenvironment, PD-L1 expression on tumor cells and other tumor-promoting cells is caused by two mechanisms, constitutive mechanism and induced mechanism, both of which depend on two binding sites of IRF-1.13 For example, in BRAFV600-mutated melanoma, PD-L1 expression is a result of cancer cells’ adaptive response to immune attack evoked by cytokines, or a constitutive expression which is a result of oncogenic processes.14 PD-L1 is rarely expressed on normal tissues but inducibly expressed on tumor site, which makes PD-L1 pathway uniquely different from other coinhibitory pathways,15 indicating that the selective expression of PD-L1 may have some association with clinical outcomes of the cancer patients and can be a selective target for antitumor therapy.

PD-1 (CD279), a PD-L1 receptor, is expressed on CD4CD8 thymocytes and CD4+CD8+ T cells during thymic development and is selectively expressed on CD4+ and CD8+ T cells, monocytes, natural killer T cells, B cells, and dendritic cells upon induction by TCR and cytokine arousal.16,17 In chronically infected mice model, high expression of PD-1 on T cells leads to T cell exhaustion and makes the exhausted CD8+ T cells lose effector function of secreting cytokines such as IL-2, IFN-γ, and TNF-α.18 Binding of PD-L1 to PD-1 leads to the formation of PD-1/TCR inhibitory microcluster that recruits SHP1/2 molecule and dephosphorylates multiple members of TCR signaling pathway, leading to the shut-off of T cell activation through induction of apoptosis, reduction of proliferation, and inhibition of cytokine secretion (Figure 1). However, whether all kinds of cancers utilize the same action mechanism of PD-L1 signaling, that is, whether different prognosis of different cancers is caused by different PD-L1 mechanisms, remains inconclusive and needs to be further explored.

Figure 1 PD-1/PD-L1 signaling: decreased CD8+ T cell proliferation, survival, and cytokine production.
Abbreviations: DC, dendritic cell; Treg, regulatory T cell; ICOS, inducible costimulator; ICOS-L, inducible costimulator-ligand; CD28, cluster of differentiation 28; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; PD-L1, programmed death-ligand 1; PD-1, programmed death-1; MHC, major histocompatibility complex; TCR, T cell receptor; IFN-γ, interferon-γ; IFN-γR, interferon-γ Receptor.

PD-1/PD-L1 pathway plays a prominent role in immune regulation by delivering inhibitory signals to maintain the balance in T cell activation, tolerance, and immune-mediated tissue damage. It exerts significant inhibitory functions in persistent antigenic stimulation environment such as exposure to self-antigen, chronic viral infection, and tumor.1921 PD-L1 can also serve as a receptor transmitting antiapoptotic signal to tumor cells to protect them from apoptosis. Moreover, Shi et al22 have demonstrated that PD-L1 may have oncogenic function during colon cancer carcinogenesis. PD-L1 not only inhibits T cell proliferation and cytokine production but also enhances T cell activation.23 The explanation of this contradictory phenomenon is unknown.

In normal tissues, PD-1 signaling in T cells regulates immune responses to decrease damage to adjacent tissue, and counteracts the development of autoimmunity by promoting tolerance to self-antigens. PD-L1 receptor is also expressed on the surface of CD4+Foxp3+ regulatory T cells (Tregs), a subset of CD4+ T cells that play a critical role in maintaining immune tolerance and weakening immune responses, to promote the development, maintenance, and immunosuppressive function of Tregs through inhibiting mTOR and AKT phosphorylation.24

Prognostic value of PD-L1 in malignancies

Table 1 summarizes the studies on the prognostic value of PD-L1 in different malignancies. Some malignancies such as hepatocellular carcinoma, pancreatic cancer (PC), gastric cancer, RCC, esophageal cancer (EC), and ovarian cancer can generate an immunosuppressive tumor microenvironment by expressing high-aggregate PD-L1 to avoid cytolysis by activated T cells. It may explain why overexpression of high-aggregate PD-L1 in tumors leads to poor prognosis in cancer patients. Interestingly, several long-term follow-up investigations have found an inverse correlation between PD-L1 expression on tumor cells and poor prognosis of patients. Additionally, in lung cancer, colorectal cancer (CRC), and melanoma, PD-L1 expression has both positive and negative prediction values. In thymoma and thymic carcinoma, squamous cell carcinoma of the lung, and cervical cancer, PD-L1 expression alone is not of prognostic value but is of significant prediction value when combined with other indicators such as CD8+/Foxp3+ T cell ratio.




Table 1 Prognostic value of PD-L1 in different malignancies
Abbreviations: TIL, tumor-infiltrating lymphocyte; IHC, immunohistochemistry; NA, not available; WHO, World Health Organization; TIMCs, tumor-infiltrating mononuclear cells; FACS, fluorescence-activated cell sorting; DCs, dendritic cells; NSCLC, non-small-cell lung cancer; RFS, relapse-free survival; VPSI, visceral pleural surface invasion; OS, overall survival; TNM, tumor–node–metastasis; CRC, colorectal cancer; mAb, monoclonal antibody; MMR, mismatch repair; Tregs, regulatory T cells; DFS, disease-free survival; MEL, melanoma; ICC, intrahepatic cholangiocarcinoma; pTNM, pathological TNM; PCR, polymerase chain reaction; PE, phycoerythrin; HCC, hepatocellular carcinoma; RCC, renal cell carcinoma; UCB, urothelial cancer of the bladder; WT, Wilms’ tumor; AH, anaplastic histology; FH, favorable histology.

Lung cancer

Two studies demonstrated that PD-L1 expression on tumor cells is correlated with poor prognosis in NSCLC patients. Both the studies detected PD-L1 expression both on membrane and in cytoplasm of tumor cells, but the cut-off value for PD-L1 immunohistochemistry (IHC) positivity was not mentioned.25,26 Azuma et al26 revealed that expression of high-aggregate PD-L1 on tumor cells is associated with EGFR gene mutations. Mu et al25 evaluated the intensity of PD-L1 expression in 109 NSCLC specimens. By IHC analysis, strong association was found between PD-L1 expression and shorter survival time in adenocarcinoma patients.

Two other studies showed a positive correlation between better clinical outcomes and PD-L1 expression. Velcheti et al27 assessed the predictive value of PD-L1 expression in two cohorts with 204 and 340 specimens, respectively. Tumor PD-L1 expression was found in 36% (Greek) and 25% (Yale) of the cases. Patients with PD-L1 expression above the detection threshold showed significantly better outcome. In 2014, Yang et al28 reported that patients with positive PD-L1 expression on tumor cell membrane had better relapse-free survival. Importantly, Boland et al29 showed that PD-L1 is not of independent prognostic value in squamous cell carcinoma of the lung. Based on the above studies, we conclude that PD-L1 has controversial predictive function in lung cancer.

Gastric cancer

Three articles reported the negative prediction value of PD-L1 in gastric cancer patients. Hou et al30 found that 70 of 111 patients had positive PD-L1 expression either on membrane or in the cytoplasm of tumor cells, and there was a positive correlation between the expression of PD-L1 and poor prognosis. The cut-off value was 10% in their study. The study by Hou et al also demonstrated that the combination of increased number of Foxp3+ Tregs and increased expression of PD-L1 is an even stronger predictor of lower overall survival (OS) rate and worse prognosis as compared to each individual factor alone. The other two studies did not mention the cut-off values of PD-L1 IHC staining; both of them showed that PD-L1 is of independent prognostic value.31,32 Wu et al31 examined 43 of 102 specimens and found that PD-L1 expression is mainly in the cytoplasm of tumor cells. Qing et al32 showed that 54 of 107 cases had positive PD-L1 expression. Both studies demonstrated that PD-L1 expression is significantly associated with invasion and lymph node metastasis, which are poor prognostic factors of tumors. In conclusion, gastric cancer patients with positive PD-L1 expression have a significantly poorer prognosis than PD-L1-negative patients.

Colorectal cancer

PD-L1 expression in CRC has not been fully addressed so far. Nevertheless, a strong correlation between PD-L1 expression on tumor cells and discrepant clinical outcomes has been observed. In CRC gene spectrum, DNA mismatch repair (MMR) status, known as MMR proficient and MMR deficient, has clinical significance in predicting the prognosis upon PD-L1 expression on tumor cells.33 MMR-proficient tumors are characterized by concurrent expression of MLH1, MSH2, and MSH6, whereas MMR-deficient tumors are characterized by lacking of expression of at least one of these markers.34 Droeser et al33 analyzed PD-L1 expression in two subtypes of CRCs, including 1,197 MMR-proficient and 223 MMR-deficient CRCs. They detected strong PD-L1 expression in 37% of MMR-proficient and in 29% of MMR-deficient CRCs. PD-L1 expression is associated with improved survival in MMR-proficient CRCs, which might be due to concomitant increase of CD8+ T cells infiltration.

In contrast, another two studies showed that positive PD-L1 expression in tumor is an independent predictor of poor CRC prognosis.22,35 Thus, the predictive value of PD-L1 expression on tumor cells is controversial in CRC patients.

Esophageal cancer

Positive correlation between PD-L1 expression and poor prognosis in EC was reported by two studies.36,37 Ohigashi et al36 selected 10% as cut-off value and illustrated that 18 of 41 positive cases express PD-L1 or PD-L2 on the plasma membrane and in the cytoplasm of cancer cells. Although no significant correlation was found between PD-L1 expression and number of tumor-infiltrating T lymphocytes, PD-L2 expression was found to be inversely correlated with number of tumor-infiltrating CD8+ T cells. They also found that the expression of either PD-L1 or PD-L2 has significant prognostic value and the combination of expression of PD-L1 and PD-L2 leads to significantly poorer prognosis in postoperative EC patients. Their result further demonstrates that the roles of PD-L1 and PD-L2 in tumor immune escape differ depending on tumor types.

In a study carried out by Chen et al,37 PD-L1 expression was found to be significantly associated with the infiltrating density of Foxp3+ Tregs, but the cut-off value of PD-L1 expression was not mentioned. They concluded that membrane PD-L1, but not nuclear PD-L1, expression is associated with poor OS in EC patients.

Pancreatic cancer

Four studies focused on PC have achieved similar results showing that PD-L1 expression in human pancreatic carcinoma tissues is associated with poor prognosis. Nomi et al8 recruited 51 PC patients and selected 10% as cut-off value of PD-L1 expression on tumor cells. They observed that PD-L1 expression is inversely correlated with number of tumor-infiltrating T lymphocytes, particularly CD8+ T cells, which might be a reason for the poor prognosis of PD-L1+ patients. Similarly, Wang et al38 also found that PD-L1 inhibits activation of CD4+ and CD8+ T cells in tumor microenvironment in spite of selecting 5% as cut-off value for PD-L1 expression. Inhibition of effector T cell function could promote tumor growth, which may explain the poor prognosis of PD-L1-positive patients. Chen et al39 confirmed that PD-L1 is an independent factor of poor prognosis and its expression is significantly associated with the stage of the tumor and preoperative serum CA199 level. Geng et al40 found that PD-L1 overexpression in human pancreatic carcinoma tissues might have associations with tumor progression and invasiveness, which has significant correlation with poor OS. Collectively, PD-L1 expression is correlated with poor clinical outcomes in PC.

PD-L1 expression as a predictive biomarker in cancer therapy

PD-1/PD-L1 pathway is a significant mechanism of immune suppression within tumor microenvironment. mAbs targeting PD-1 or PD-L1 could block the PD-1/PD-L1 pathway and enhance T cell functions. Thus, mAbs to PD-1 and PD-L1, as well as PD-L2 fusion protein, are widely tested in different clinical trials. Pidilizumab, lambrolizumab, nivolumab, and AMP-224 are mAbs targeting PD-1, whereas BMS-936559, MEDI4736, MPDL3280A, and MSB0010718C are mAbs to PD-L1.41 These mAbs were used in the treatment of malignancies including melanoma, NSCLC, RCC, bladder cancer, CRC, and gastric cancer. The overall response rates achieved was 16%–100%.3,42 Consequently, an effective predictive biomarker is needed to select “real” patients who will benefit from cancer immunotherapy while avoiding unnecessary toxicity. Tumor PD-L1 expression as a predictive biomarker has been evaluated in many clinical trials. For example, CheckMate 03743 study confirmed that nivolumab has better clinical efficacy than chemotherapy. Weber et al43 randomly allocated 272 patients to nivolumab and 133 to investigator’s choice of chemotherapy. The pretreatment PD-L1-positive number was 134 (49%) and 67 (50%), respectively. Confirmed objective response rate (ORR) was found in 31.7% of the first 120 patients in the nivolumab group versus 10.6% of 47 patients in the group that received investigator’s choice of chemotherapy. Importantly, the complete response rates were 3.3% versus 0%. A Phase I expansion study was implemented by Powles et al44 to investigate the responsiveness of PD-L1-positive and PD-L1-negative patients to MPDL3280A. The PD-L1-positive patients achieved 43% (95% confidence interval [CI]: 26%–63%) response rate, whereas the PD-L1-negative patients achieved a response rate of 11% (95% CI: 4%–26%), demonstrating the therapeutic activity of MPDL3280A in PD-L1-positive patients with urothelial bladder cancer. Both the studies demonstrated that tumor PD-L1 expression is an effective predictor of the outcomes of cancer immunotherapy. Nevertheless, the predictive value of PD-L1 is not consistent in cancer patients. For instance, in Phase III trials of CheckMate 01745 and CheckMate 057,46 the clinical efficacy of nivolumab versus docetaxel in previously treated advanced or metastatic squamous NSCLC and non-squamous NSCLC was evaluated, respectively. The nivolumab group achieved longer OS (9.2 versus 6.0 months [P=0.00025] and 12.2 versus 9.4 months [P=0.0015], respectively) and higher ORR (20% versus 9% [P=0.0083] and 19% versus 12% [P=0.0246], respectively) than patients treated with docetaxel in two studies, but the better progression-free survival was only achieved in squamous NSCLC (CheckMate 017).45 Importantly, the beneficial effect of nivolumab in squamous NSCLC is irrelevant to PD-L1 expression, whereas in non-squamous NSCLC, PD-L1 expression is predictive of the benefit of nivolumab.46 Moreover, some PD-L1-negative patients also respond to PD-1/PD-L1 blockade therapy. Therefore, using tumor PD-L1 expression as exclusionary predictive biomarker for the outcome of PD-1/PD-L1 blockade therapy has its limitations.47

mAbs targeting PD-1/PD-L1 pathway have achieved impressive response rates in patients with melanoma, NSCLC, RCC, and bladder cancer, and the value of PD-L1 as a predictive biomarker for the outcomes of mAb therapy has been demonstrated in many studies.35 Other predictive biomarkers for the prognosis of PD-L1 mAb immunotherapy in cancers have also been investigated. In 2015, ASCO, a Phase II study, confirmed the first gene predictive biomarker – MMR deficiency could effectively predict PD-1 blockade efficacy. In 41 patients with or without MMR deficiency, the ORR was 40% for MMR-deficient CRC patients and 0% for MMR-proficient CRC patients. The progression-free survival rate was 78% for MMR-deficient CRC patients and 11% for MMR-proficient CRC patients.48 More biomarkers should be investigated to facilitate the accurate selection of patients who can benefit from PD-1/PD-L1 blockade therapy.

Explanations of PD-L1 prognostic and predictive value

IHC-based detection of PD-L1 has limitations because of its subjectivity in determining a clear definition of “positive” tumor PD-L1 staining.49,50 Antibodies used in different studies include M1H1, 5H1, 5H1-A3, 2H11, 27A2, 405.9A11, and E1L3N.6,10,12,31,33,51,52 Different PD-L1 antibody clones can be a reason for lower PD-L1 expression in some studies. In addition to technical issues with IHC, temporal and spatial factors should also be considered when assessing PD-L1 in cancers. Specimens that were obtained when PD-L1 overexpression in tumor microenvironment has already taken place or patients’ specimens that missed the pertinent tumor–immune interface may lead to a bias in PD-L1’s predictive value in cancers.53 Furthermore, interferon-γ secreted by tumor-infiltrating lymphocytes may cause upregulation of PD-L1 on tumor cells, leading to the induction of T cell apoptosis via PD-L1 and PD-1 interaction. Collectively, the prognostic value of PD-L1 IHC relies on the time of biopsy that is associated with the development of the nidus and is related to previous therapies including chemotherapy or radiotherapy. Deng et al54 demonstrated that tumor PD-L1 expression is upregulated after irradiation in mouse models. Therefore, single-time point evaluation of PD-L1 expression may not reflect the real condition, and multiple sites sampling is necessary for the determination of PD-L1 expression.

Spatial impact is another consideration when assessing PD-L1 expression in cancers. PD-L1 expression status may differ in primary lesions versus metastatic lesions due to tumor heterogeneity. PD-L1 expression has two patterns, focal expression and diffuse expression.55 Even from the same sample, impertinent biopsy may result in a bias due to the focal nature of PD-L1 expression in many tumors. Assessment of PD-L1 expression in tumor or peritumor is also a question. Thus, selection of the optimum site for biopsy for assessing PD-L1 expression status remains challenging and needs further studies.

Difficulties in comparing different, sometimes even contrary, results also arise from the following considerations: available data are retrospective, patients have different clinical characteristics, tumor samples from different tumor types or different locations of the same tumor are heterogeneous, and PD-L1 positivity is defined by membrane and/or cytoplasmic PD-L1 immunostaining. Several studies have demonstrated that only cell membrane-expressed PD-L1 has biological significance.56 Therefore, it is more reasonable to analyze correlations between membrane PD-L1 protein, rather than intracellular PD-L1 protein or mRNA, and clinical outcomes.

MMR, the first gene predictive biomarker that bridges the immunotherapy and genomics, effectively predicts PD-1 blockade efficacy in various cancers. It is necessary to develop more genetic methods to improve the effective prediction of cancer immunotherapy, and select “real” patients who are most likely to benefit from the immunotherapy. As the candidates of predictive marker, CD8+ T lymphocytes and IFN-γ may be evaluated in consideration of their importance in tumor microenvironment.

Conclusion

Studies have demonstrated that binding of tumor PD-L1 to its receptor PD-1 on T cell surface inhibits infiltrating T cell activation and subsequent lysis of tumor cells. PD-L1 expression in tumors strongly correlates with poor prognosis in gastric cancer, hepatocellular carcinoma, RCC, EC, PC, and ovarian cancer.30,37,39,5759 However, opposite results have been observed in breast cancer and merkel cell carcinoma, where tumor PD-L1 expression correlates with a better prognosis.60,61 In lung cancer, CRC, and melanoma, PD-L1 expression has both positive and negative prediction value.33,35,6264 The controversy in PD-L1’s diagnostic and predictive value may be due to the following reasons. First, IHC-based detection of PD-L1 has technical issues, and the results may not accurately reflect the real PD-L1 expression status. Second, detection of PD-L1 expression in tumors is affected by temporal and spatial factors, leading to erroneous interpretation of the results. In addition, PD-L1 expression heterogeneity should also be taken into consideration. All these factors illustrate the limitation of using tumor PD-L1 expression as an exclusive biomarker for cancer immunotherapy. However, we cannot ignore the value of PD-L1 expression in selecting patients who will benefit from immunotherapy. Many clinical trials have demonstrated that immunotherapy significantly improves progression-free survival in patients. Remarkably, the grade 3 or 4 adverse events were evidently decreased compared to chemotherapy.45,9193

Other effective biomarkers such as gene marker or combined indexes and improved understanding of tumor microenvironment are needed to accurately determine which patients will benefit from PD-1/PD-L1 pathway blockade therapy and to avoid the unnecessary autoimmune side effects from overtreatment.

Disclosure

The authors report no conflicts of interest in this work.


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