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ORIGINAL ARTICLE
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Good prognostic factor in patients with nonmetastatic nasopharyngeal carcinoma: Programmed death ligand-1 expression in tumor cells


1 Department of Oncology, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
2 Department of Pathology, Gazi University Medical University Hospital, Ankara, Turkey
3 Department of Oncology, Gazi University Medical University Hospital, Ankara, Turkey
4 Department of Pathology, Dr. Abdurrahman Yurtaslan Ankara Oncology Hospital, Ankara, Turkey
5 Department of Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Hospital, Ankara, Turkey
6 Department of Pathology, Ankara Numune Training and Research Hospital, Ankara, Turkey
7 Department of Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey

Date of Submission16-Sep-2019
Date of Decision17-Oct-2019
Date of Acceptance12-Nov-2019
Date of Web Publication22-Jul-2020

Correspondence Address:
Hayriye Sahinli,
Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ömer Halis Demir Street, Ankara, Altındaǧ
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_759_19

 > Abstract 


Purpose: Programmed death ligand-1 (PD-L1) is the main ligand for programmed death-1 (PD-1), and is one of the major targets for cancer immunotherapy. Only a few studies are available for the clinical significance of PD-1/PD-L1 in nasopharyngeal carcinoma (NPC). There is a controversial association between PD-L1 expression and survival in NPC. This study aimed at defining any potential association between PD-L1 expression in tumor cells (TCs) and prognosis in NPC.
Patients and Methods: A total of seventy NPC patients treated between January 2008 and December 2016 were included in the study. PD-L1 expression was assessed by immunohistochemistry (IHC) in tumor specimens. The IHC assay was considered positive if ≥5% of TCs are stained. Clinicopathological variables were documented. Variables included in the analysis were PD-L1 expression, clinicopathological characteristics, and prognosis.
Results: The estimated 5-year overall survival (OS) rate was 62%. Nearly 55.7% (n = 39) of the TCs tested positive for PD-L1 expression. No associations were found between the level of PD-L1 in TCs and clinicopathological characteristics. Comparisons between patients with PD-L1-positive tumors and PD-L1-negative tumors revealed that OS was statistically significantly longer in patients with PD-L1-positive tumors as assessed by the univariate Cox regression analysis (hazard ratio [HR], 0.378; 95% confidence interval, 0.158–0.905; P = 0.029) and Kaplan–Meier curves (P = 0.023).
Conclusion: PD-L1 expression is an important prognostic factor in NPC. PD-L1 expression positively correlates with survival.

Keywords: Expression, nasopharyngeal carcinoma, prognosis, programmed death ligand-1



How to cite this URL:
Sahinli H, Akyürek N, Yılmaz M, Kandemir O, Duran AO, Kulaçoǧlu S, Uçar G, Acar E, Özet A, Öksüzoǧlu O B, Özdemir NY. Good prognostic factor in patients with nonmetastatic nasopharyngeal carcinoma: Programmed death ligand-1 expression in tumor cells. J Can Res Ther [Epub ahead of print] [cited 2020 Aug 12]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=290471




 > Introduction Top


Nasopharyngeal carcinoma (NPC) arises from the surface epithelium of nasopharynx. NPC differs from other epithelial tumors of the head-and-neck region in terms of histology, clinical presentation, and response to treatment.[1],[2],[3] NPC is associated with Epstein–Barr virus (EBV), and its incidence in endemic regions such as South China is 30–80/100,000/year.[2] NPC is highly sensitive to radiation therapy and chemotherapy. Although the 5-year local control rate and 5-year disease-free rate increased up to 95% and 77%, respectively, owing to recent advances in imaging modalities and radiation therapy in patients with early-stage disease, outcomes in T4 disease are not encouraging.[4],[5],[6] Furthermore, NPC is among cancers showing a high propensity to distant metastases. Therefore, new treatments are needed to improve survival.

NPC is characterized by a significant lymphocytic infiltration in primary tumors.[3],[7],[8] Programmed cell death protein 1 is an immunosuppressive receptor expressed by T cells.[9] Programmed death ligand-1/programmed death-1 (PD-L1/PD-1) binding in tumor cells (TCs) reduces T-cell activation.[9],[10] Encouraging results have been obtained with treatments developed to suppress PD-1 and its ligand PD-L1.[11],[12],[13]

PD-L1 expression can be observed in a number of cancer types including esophageal, gastrointestinal, pancreas, breast, lung, and kidney cancers. PD-1/PD-L1 protein expression has been linked with aggressive histological types and poor prognosis in many tumor types.[12],[13],[14],[15],[16],[17] On the other hand, PD-L1 expression has been found to be a good prognostic factor in squamous cell carcinoma of lung and breast cancers.[3],[18]

The prognostic significance of PD-L1 expression in NPC has been investigated in a number of studies. In a study conducted by Zhang et al., PD-L1 expression has been found to be associated with poor survival.[5] Unlike this study, a positive correlation was found between PD-L1 expression and survival in patients with nonmetastatic NPC in a study conducted by Lee et al.[19] Therefore, the prognostic role of PD-L1 in TCs is not clear in patients with NPC, and further studies are needed to clarify whether PD-L1 has a prognostic role. This study aimed at defining any potential association between PD-L1 expression in TCs and prognosis.


 > Patients and Methods Top


This study included a total of seventy patients who were diagnosed with nonmetastatic NPC based on tumor biopsies taken between January 2008 and December 2016 at Ankara Gazi University Hospital, Dr. Abdurrahman Yurtaslan Teaching Hospital, and Ankara Numune Teaching Hospital, Ankara. Formalin-fixed paraffin-embedded tissue samples were obtained from biopsy specimens at diagnosis. Data obtained from patient files included age, sex, tumor stage, histological diagnosis, and smoking history. This study protocol was approved by the Ethics Committee of Ankara Numune Teaching Hospital. Antibodies used in this study were supplied by Bristol-Myers Squibb (Istanbul, Turkey).

Immunohistochemical staining

Immunohistochemical staining of 4-μm sections from formalin-fixed paraffin-embedded archived tissue of nasopharyngeal biopsies or excision specimens of tumor was performed with the antibody anti-PD-L1 (SP263 Ventana Medical Systems) using the standard protocol for routine diagnostic specimens.

The percentages of TCs positive for PD-L1 were evaluated. Immunohistochemistry (IHC) staining in 0%–5% of TCs was considered negative and staining in ≥5% of TCs was considered positive.

The ratios of PD-L1-positive TCs in all the carcinoma cells were evaluated by microscopic observation (TC scores). The tumor area was defined as the area occupied by viable TCs and their associated intratumoral and contiguous peritumoral stroma [Figure 1]. The necrotic areas were excluded from the scoring area. Although cases with <100 viable TCs were excluded from the present study, all the examined cases contained >100 TCs. Negative reagent controls were evaluated in each case by confirming the acceptable level of background staining.
Figure 1: High level of programmed death ligand-1 expression in a biopsy from a patient with nasopharyngeal carcinoma (IHC, ×400)

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Statistical analysis

Pearson's Chi-square test was used to assess associations between PD-L1 expression and clinicopathological characteristics. Survival curves were depicted using the Kaplan–Meier's method and compared using the log-rank test. The Cox proportional hazard analysis was performed to calculate hazard ratios (HR) and 95% confidence interval (CIs) to evaluate the associations between tumor PD-L1 expressions and survival outcome. Overall survival (OS) of patients following treatment was calculated by considering all death events. An univariate analysis was performed using the Cox proportional hazards model to define prognostic factors. Multivariate analysis was not performed because there was only one significant factor in univariate survival analysis. The SPSS program version 20.0 (SPSS Inc, Chicago, IL, USA) was used for all analyses. Statistical significance level was set at P < 0.05.


 > Results Top


The seventy patients with nonmetastatic NPC were included in this study. The median age in the study group was 52 (18–76) years. Fourteen patients were female and 56 patients were male. According to the American Joint Committee on Cancer staging system 7th edition (AJCC 7), 22.7% of the patients (15 patients) had Stage I or II disease and 77.3% (51 patients) had Stage III or IV a, b disease. The median follow-up duration was 34 (1–188 months) months. Nearly 31.4% of patients (n = 22) died during the follow-up. The estimated 5-year OS rate was 62%. The median OS was not reached. PD-L1 expressions were assessed in immunohistochemically stained specimens from the seventy patients. Almost 55.7% (n = 39) of the TCs tested positive for PD-L1 expression. Associations between PD-L1 expression in TCs in NPC and clinicopathological characteristics (age, sex, smoking history, and TNM stage) were assessed. Seventy patients were categorized into PD-L1-positive and PD-L1-negative groups based on the level of PD-L1 expression in TCs. The cutoff value was set at ≥5% for a positive PD-L1 expression. No associations were found between PD-L1 levels in TCs and clinicopathological characteristics [Table 1]. The comparisons between PD-L1-positive group and PD-L1-negative group revealed that OS was significantly longer in patients who tested positive for PD-L1 as indicated by univariate Cox regression analysis [HR, 0.378; 95% CI, 0.158–0.905; P = 0.029, [Table 2] and Kaplan–Meier curves [P = 0.023, [Figure 2].
Table 1: Associations between programmed death ligand-1 expression in tumor cells and clinicopathological features in patients with nasopharyngeal carcinomas

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Table 2: The Cox proportional regression analysis for the prediction of overall survival in patients with nasopharyngeal carcinoma

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Figure 2: Overall survival curve for patients stratified by positive and negative programmed death ligand-1 expression in tumor cells

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 > Discussion Top


NPC is among the malignancies associated with EBV that are known to have higher metastatic potential compared to other head-and-neck tumors.[5],[19] Therefore, it is important to identify patients who are at high risk for relapse after primary treatment.

In this study, we analyzed associations between tumor PD-L1 expression and clinicopathological characteristics as well as OS.

PD-L1 is an immunomodulatory cell surface glycoprotein primarily expressed by antigen presenting cells and TCs.[20] Once the PD-L1 ligand binds to PD-1, it may inhibit T cell proliferation and cytokine secretion.[21],[22],[23] Increased tumor PD-L1 expression has been demonstrated in a number of malignancies including glioblastoma and melanoma.[24],[25],[26],[27],[28],[29] In recent clinical studies, a better response to treatment with anti-PD-1 agents has been reported in patients with higher PD-L1 expression.[12],[30] PD-L1 expression may help identifying patients who may benefit from immunomodulatory agents.[31],[32],[33] The role of PD-L1 expression in TCs as a prognostic factor is not clear in various malignancies.[34] The use of PD-L1 expression as a marker is controversial due to the use of different antibodies, assessment methods, and various threshold values. A number of studies have reported a negative correlation between tumor PD-L1 expression and OS, whereas a positive correlation has been reported between tumor PD-L1 expression and OS in specific tumors such as colorectal cancer, non-small cell lung cancer, and melanoma.[35],[36],[37],[38],[39],[40] These differences indicate that the association between PD-L1 expression and host immune response may differ in various cancer types. PD-L1 expressed by TCs is regulated by intrinsic immune resistance and adaptive resistance mechanisms.[41],[42] Intrinsic resistance results in increased PD-L1 expression in TCs secondary to oncogenic signals including tumor suppressive PTEN (phosphatase and tensin homolog) gene mutation or deletion, pro-oncogenic PI3K (phosphatidylinositol 3-kinase) pathway activation, and dysregulation of AKT/mTOR and MAPK (mitogen-activated protein kinase, MEK/ERK) pathways.[43],[44],[45] This mechanism indicates that PD-1/PD-L1 checkpoint blockage in preexisting tumor antigen-specific T cells leads to T cell proliferation, intratumoral infiltration, and enhanced effector function.[46],[47] Adaptive immunity occurs once PD-L1 is upregulated in TCs in response to interferon gamma secreted by CD8 T cells during active antitumor immune response.[41],[47],[48],[49] Consequently, PD-L1 expression does not directly correlate with tumoral evasion. What causes the expression of inflammatory markers may be an indicator of ongoing immune response against tumor.[36],[37],[38],[39] In a previous study, a better immune surveillance of PD-L1 expression in squamous cell carcinoma of larynx was supported by this mechanism. A statistically significant positive correlation was found between tumor PD-L1 expression and survival in our study.

In a study conducted by Zhang et al., the expression of PD-1 alone or co-expression with PD-L1 resulted in a poor disease-free survival.[5] However, that study included patients with Stage 4c metastatic disease, whereas our study did not. In a study conducted by Zhu et al., a positive correlation was found between tumor PD-L1 expression level and OS in patients with NPC. In that study, the cutoff value for a positive PD-L1 expression level was considered at ≥5%.[41] No consensus has been achieved yet to define a positive staining. There is an unmet need for standardized test procedures and consistent IHC scoring criteria. Greater than 5% staining in TCs, which was considered positive in previous studies in lung cancer, has gained popularity. We also used a cutoff value of staining in ≥5% TCs to consider a test positive for PD-L1. In our study, 55.7% of (n = 39) specimens tested positive for PD-L1. In previous studies, the proportion of PD-L1-positive cells varied between 25% and 97%.[5],[12],[41] The proportion of PD-L1-positive cells in our study was similar to the proportions detected in previous studies.


 > Conclusion Top


The prognostic effects of tumor PD-L1 expression have remained unclear in previous studies investigating the effects of PD-L1 expression on OS. PD-L1 is frequently expressed in NPC. In our study, PD-L1-positive TCs were found to be an independent prognostic factor, and a positive correlation was found between tumor PD-L1 expression and OS. The limitations of our study included the retrospective design of the study and small sample size. Prospective studies with larger sample size are warranted.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Chan AT, Teo PM, Johnson PJ. Nasopharyngeal cancer. Cancer Treat Res 2003;114:275-93.  Back to cited text no. 1
    
2.
Strazzulla A, Barreca GS, Giancotti A, Pisani V, Costa C, Zicca E, et al. Nasopharyngeal carcinoma: Review of the literature with a focus on therapeutical implications. Infez Med 2015;23:224-9.  Back to cited text no. 2
    
3.
Zhou Y, Shi D, Miao J, Wu H, Chen J, Zhou X, et al. PD-L1 predicts poor prognosis for nasopharyngeal carcinoma irrespective of PD-1 and EBV-DNA load. Sci Rep 2017;7:43627.  Back to cited text no. 3
    
4.
Ma BB, Hui EP, Chan AT. Systemic approach to improving treatment outcome in nasopharyngeal carcinoma: Current and future directions. Cancer Sci 2008;99:1311-8.  Back to cited text no. 4
    
5.
Zhang J, Fang W, Qin T, Yang Y, Hong S, Liang W, et al. Co-expression of PD-1 and PD-L1 predicts poor outcome in nasopharyngeal carcinoma. Med Oncol 2015;32:86.  Back to cited text no. 5
    
6.
Xiao WW, Huang SM, Han F, Wu SX, Lu LX, Lin CG, et al. Local control, survival, and late toxicities of locally advanced nasopharyngeal carcinoma treated by simultaneous modulated accelerated radiotherapy combined with cisplatin concurrent chemotherapy: Long-term results of a phase 2 study. Cancer 2011;117:1874-83.  Back to cited text no. 6
    
7.
Khanna R, Busson P, Burrows SR, Raffoux C, Moss DJ, Nicholls JM, et al. Molecular characterization of antigen-processing function in nasopharyngeal carcinoma (NPC): Evidence for efficient presentation of Epstein-Barr virus cytotoxic T-cell epitopes by NPC cells. Cancer Res 1998;58:310-4.  Back to cited text no. 7
    
8.
Pai S, O'Sullivan B, Abdul-Jabbar I, Peng J, Connoly G, Khanna R, et al. Nasopharyngeal carcinoma-associated Epstein-Barr virus-encoded oncogene latent membrane protein 1 potentiates regulatory T-cell function. Immunol Cell Biol 2007;85:370-7.  Back to cited text no. 8
    
9.
Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol 2009;10:1185-92.  Back to cited text no. 9
    
10.
Carreno BM, Collins M. The B7 family of ligands and its receptors: New pathways for costimulation and inhibition of immune responses. Annu Rev Immunol 2002;20:29-53.  Back to cited text no. 10
    
11.
Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 2012;24:207-12.  Back to cited text no. 11
    
12.
Li YF, Ding JW, Liao LM, Zhang ZL, Liao SS, Wu Y, et al. Expression of programmed death ligand-1 predicts poor outcome in nasopharyngeal carcinoma. Mol Clin Oncol 2017;7:378-82.  Back to cited text no. 12
    
13.
Lu J, Lee-Gabel L, Nadeau MC, Ferencz TM, Soefje SA. Clinical evaluation of compounds targeting PD-1/PD-L1 pathway for cancer immunotherapy. J Oncol Pharm Pract 2015;21:451-67.  Back to cited text no. 13
    
14.
Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 2008;8:467-77.  Back to cited text no. 14
    
15.
Flies DB, Chen L. The new B7s: Playing a pivotal role in tumor immunity. J Immunother 2007;30:251-60.  Back to cited text no. 15
    
16.
Muenst S, Schaerli AR, Gao F, Däster S, Trella E, Droeser RA, et al. Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat 2014;146:15-24.  Back to cited text no. 16
    
17.
Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 2006;66:3381-5.  Back to cited text no. 17
    
18.
Baptista MZ, Sarian LO, Derchain SF, Pinto GA, Vassallo J. Prognostic significance of PD-L1 and PD-L2 in breast cancer. Hum Pathol 2016;47:78-84.  Back to cited text no. 18
    
19.
Lee VH, Lo AW, Leung CY, Shek WH, Kwong DL, Lam KO, et al. Correlation of PD-L1 expression of tumor cells with survival outcomes after radical ıntensity-modulated radiation therapy for non-metastatic nasopharyngeal carcinoma. PLoS One 2016;11:e0157969.  Back to cited text no. 19
    
20.
Pathmanathan R, Prasad U, Sadler R, Flynn K, Raab-Traub N. Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl J Med 1995;333:693-8.  Back to cited text no. 20
    
21.
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26:677-704.  Back to cited text no. 21
    
22.
Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 2001;193:839-46.  Back to cited text no. 22
    
23.
Obeid JM, Erdag G, Smolkin ME, Deacon DH, Patterson JW, Chen L, et al. PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome. Oncoimmunology 2016;5:e1235107.  Back to cited text no. 23
    
24.
Tamura H, Dong H, Zhu G, Sica GL, Flies DB, Tamada K, et al. B7-H1 costimulation preferentially enhances CD28-independent T-helper cell function. Blood 2001;97:1809-16.  Back to cited text no. 24
    
25.
Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, et al. Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A 2004;101:17174-9.  Back to cited text no. 25
    
26.
Ghebeh H, Mohammed S, Al-Omair A, Qattan A, Lehe C, Al-Qudaihi G, et al. The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: Correlation with important high-risk prognostic factors. Neoplasia 2006;8:190-8.  Back to cited text no. 26
    
27.
Loos M, Giese NA, Kleeff J, Giese T, Gaida MM, Bergmann F, et al. Clinical significance and regulation of the costimulatory molecule B7-H1 in pancreatic cancer. Cancer Lett 2008;268:98-109.  Back to cited text no. 27
    
28.
Karim R, Jordanova ES, Piersma SJ, Kenter GG, Chen L, Boer JM, et al. Tumor-expressed B7-H1 and B7-DC in relation to PD-1+T-cell infiltration and survival of patients with cervical carcinoma. Clin Cancer Res 2009;15:6341-7.  Back to cited text no. 28
    
29.
Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res 2004;10:5094-100.  Back to cited text no. 29
    
30.
Avril T, Saikali S, Vauleon E, Jary A, Hamlat A, De Tayrac M, et al. Distinct effects of human glioblastoma immunoregulatory molecules programmed cell death ligand-1 (PDL-1) and indoleamine 2,3-dioxygenase (IDO) on tumour-specific T cell functions. J Neuroimmunol 2010;225:22-33.  Back to cited text no. 30
    
31.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-54.  Back to cited text no. 31
    
32.
Teixidó C, Karachaliou N, González-Cao M, Morales-Espinosa D, Rosell R. Assays for predicting and monitoring responses to lung cancer immunotherapy. Cancer Biol Med 2015;12:87-95.  Back to cited text no. 32
    
33.
Tripathi A, Drake CG, Harshman LC. Harnessing the PD-1 pathway in renal cell carcinoma: Current evidence and future directions. BioDrugs 2014;28:513-26.  Back to cited text no. 33
    
34.
Sakane T, Murase T, Okuda K, Takino H, Masaki A, Oda R, et al. A comparative study of PD-L1 immunohistochemical assays with four reliable antibodies in thymic carcinoma. Oncotarget 2018;9:6993-7009.  Back to cited text no. 34
    
35.
Patel SP, Kurzrock R. PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy. Mol Cancer Ther 2015;14:847-56.  Back to cited text no. 35
    
36.
Lipson EJ, Vincent JG, Loyo M, Kagohara LT, Luber BS, Wang H, et al. PD-L1 expression in the Merkel cell carcinoma microenvironment: Association with inflammation, Merkel cell polyomavirus and overall survival. Cancer Immunol Res 2013;1:54-63.  Back to cited text no. 36
    
37.
Droeser RA, Hirt C, Viehl CT, Frey DM, Nebiker C, Huber X, et al. Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer 2013;49:2233-42.  Back to cited text no. 37
    
38.
Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, et al. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest 2014;94:107-16.  Back to cited text no. 38
    
39.
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 2012;4:127ra37.  Back to cited text no. 39
    
40.
Wang X, Teng F, Kong L, Yu J. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther 2016;9:5023-39.  Back to cited text no. 40
    
41.
Zhu Q, Cai MY, Chen CL, Hu H, Lin HX, Li M, et al. Tumor cells PD-L1 expression as a favorable prognosis factor in nasopharyngeal carcinoma patients with pre-existing intratumor-infiltrating lymphocytes. Oncoimmunology 2017;6:e1312240.  Back to cited text no. 41
    
42.
Ritprajak P, Azuma M. Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma. Oral Oncol 2015;51:221-8.  Back to cited text no. 42
    
43.
Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 2007;13:84-8.  Back to cited text no. 43
    
44.
Outh-Gauer S, Alt M, Le Tourneau C, Augustin J, Broudin C, Gasne C, et al. Immunotherapy in head and neck cancers: A new challenge for immunologists, pathologists and clinicians. Cancer Treat Rev 2018;65:54-64.  Back to cited text no. 44
    
45.
Xu-Monette ZY, Zhang M, Li J, Young KH. PD-1/PD-L1 blockade: Have we found the key to unleash the antitumor ımmune response? Front Immunol 2017;8:1597.  Back to cited text no. 45
    
46.
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;515:568-71.  Back to cited text no. 46
    
47.
Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, et al. Up-regulation of PD-L1, IDO, and T (regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med 2013;5:200ra116.  Back to cited text no. 47
    
48.
Taube JM, Young GD, McMiller TL, Chen S, Salas JT, Pritchard TS, et al. Differential expression of ımmune-regulatory genes associated with PD-L1 display in melanoma: Implications for PD-1 pathway blockade. Clin Cancer Res 2015;21:3969-76.  Back to cited text no. 48
    
49.
Liu YJ, Tsang NM, Hsueh C, Yeh CJ, Ueng SH, Wang TH, et al. Low PD-L1 expression strongly correlates with local recurrence in Epstein–Barr virus-positive nasopharyngeal carcinoma after radiation-based therapy. Cancers (Basel) 2018;10. pii: E374.  Back to cited text no. 49
    


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