|Ahead of print publication
Good prognostic factor in patients with nonmetastatic nasopharyngeal carcinoma: Programmed death ligand-1 expression in tumor cells
Hayriye Sahinli1, Nalan Akyürek2, Mukaddes Yılmaz3, Olcay Kandemir4, Ayşe Ocak Duran5, Sezer Kulaçoǧlu6, Gökhan Uçar7, Elif Acar2, Ahmet Özet3, O Berna Ç. Öksüzoǧlu5, Nuriye Y Özdemir7
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 Submission||16-Sep-2019|
|Date of Decision||17-Oct-2019|
|Date of Acceptance||12-Nov-2019|
|Date of Web Publication||22-Jul-2020|
Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ömer Halis Demir Street, Ankara, Altındaǧ
Source of Support: None, Conflict of Interest: None
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|| |
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.,, NPC is associated with Epstein–Barr virus (EBV), and its incidence in endemic regions such as South China is 30–80/100,000/year. 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.,, 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.,, Programmed cell death protein 1 is an immunosuppressive receptor expressed by T cells. Programmed death ligand-1/programmed death-1 (PD-L1/PD-1) binding in tumor cells (TCs) reduces T-cell activation., Encouraging results have been obtained with treatments developed to suppress PD-1 and its ligand PD-L1.,,
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.,,,,, 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.,
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. 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. 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|| |
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 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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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|| |
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|| |
NPC is among the malignancies associated with EBV that are known to have higher metastatic potential compared to other head-and-neck tumors., 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. Once the PD-L1 ligand binds to PD-1, it may inhibit T cell proliferation and cytokine secretion.,, Increased tumor PD-L1 expression has been demonstrated in a number of malignancies including glioblastoma and melanoma.,,,,, In recent clinical studies, a better response to treatment with anti-PD-1 agents has been reported in patients with higher PD-L1 expression., PD-L1 expression may help identifying patients who may benefit from immunomodulatory agents.,, The role of PD-L1 expression in TCs as a prognostic factor is not clear in various malignancies. 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.,,,,, 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., 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.,, 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., 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.,,, 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.,,, 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. 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%. 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%.,, The proportion of PD-L1-positive cells in our study was similar to the proportions detected in previous studies.
| > Conclusion|| |
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
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]