The prognostic role of PD-L1 expression for survival in head and neck squamous cell carcinoma: A systematic review and meta-analysis
Introduction
Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies, with an annual incidence of over 600,000 worldwide [1]. Despite recent advances in multidisciplinary regimens, treatment outcomes remained poor and barely improved over the past decades. Even with an accumulated knowledge of cancer genomics, the identification of clinical prognostic factors has still been a major challenge to improve risk stratification and personalized treatment in HNSCC [2].
Other than the conventional studies of biomarkers on tumor cells, new insights have emphasized the prospective predictive role of tumor immune microenvironment [3], [4]. HNSCC is typically characterized by diverse profiles of tumor-infiltrating lymphocytes (TILs), which render tumor cells in the distinct “inflamed” or “non-inflamed” condition [5], [6]. Since different cohorts of TILs display different functions, the prognostic values of TILs are not unchanging in different settings [5], [7]. For instance, as the most prominent cohort, the cytotoxic CD8+ T cells tend to exert an anti-cancer effect through recognizing and killing cancer cells, therefore underlining the positive prognostic role of CD8+ T cells in HNSCC [8].
The anti-cancer functions of CD8+ T cells, however, can be counterbalanced by the compensatory expression of programmed death-ligand 1 (PD-L1) on tumor cells [9], [10]. The PD-L1 is a transmembrane protein that can be triggered by interferon gamma (IFNγ), which is predominantly released from activated CD8+ T cells in the tumor microenvironment [11]. The overexpression of PD-L1, in turn, can induce T cell anergy and apoptosis by interacting with programmed death protein 1 (PD-1), which is an immune checkpoint expressed on the surface of immune cells [11], [12]. Generally, the PD-L1 serves as an immune gatekeeper in regulating the dynamic interrelationship between TILs and tumor cells, which indicates a potential prognostic role of PD-L1 for survival in HNSCC.
Considering the profound roles of PD-1/PD-L1, the cancer immunotherapy based on PD-1/PD-L1 checkpoint blockade has been developed to renovate CD8+ T cells in advanced or refractory cancers [13], [14]. In the most recent clinical trials, the overall response rates to PD-1/PD-L1 blockade were 13.3–17.7% in recurrent and metastatic HNSCC, and survival outcomes were improved with a prolonged duration of response [15], [16], [17]. Moreover, in patients with positive PD-L1 expression, an improved response rate was observed when compared to patients with negative PD-L1, although further clinical verification shall be required [16], [17], [18]. Taken all together, before clarifying the predictive role of PD-L1 for PD-1/PD-L1 blockade immunotherapy, it is worthwhile to investigate the prognostic role of PD-L1 expression for survival in patients with HNSCC.
Expression of PD-L1 in cellular membrane or cytoplasm of tumor cells, detected by immunohistochemistry (IHC) assays, has been widely investigated in recent years. IHC was used to semi-quantitatively examine the localization and expression of PD-L1 in tumor tissues [19]. Numerous studies have been published, showing inconsistent findings regarding the prognostic value of PD-L1 expression for survival in HNSCC. Compelling evidence is needed to further guide clinical practice and research. Therefore, in the present study, we aimed to conduct a systematic review and meta-analysis to evaluate comprehensively the prognostic role of PD-L1 expression detected by IHC for survival in patients with HNSCC.
Section snippets
Search strategy
We performed a comprehensive search in PubMed, Embase, Web of Science, Cochrane Library, and Scopus for relevant studies using different combinations of keywords from the following four domains: head and neck, squamous cell carcinoma, PD-L1, and prognosis. The detailed search strategy in PubMed is shown in Supplementary Table 1. All studies published before March 31, 2018 were screened in the initial stage by title and abstract. Any potential studies were subsequently reviewed by full-text
Selection of studies
Of 3424 records initially identified from database searching, and 3 additional reports retrieved through reference lists, 3056 records were retained after duplicates removed. By title and abstract screening, 2997 studies were excluded in the first stage. The remaining 59 articles were reviewed by full text in the second stage, among which 36 were excluded due to various reasons as shown in Fig. 1. According to the predefined inclusion and exclusion criteria, 23 studies with 25 independent
Overall survival (OS)
A total of 19 studies with 21 patient cohorts investigated the prognostic role of PD-L1 expression for OS in HNSCC (Fig. 3). Due to the significant heterogeneity (I2 = 76.0%, p < 0.001), the random-effect analysis was used. No significant difference was found for OS comparing the PD-L1-positive and -negative patients (HR: 0.98; 95% CI: 0.71–1.37; p = 0.93). In subgroup analyses based on different primary cancer sites, the prognostic roles of PD-L1 expression for OS were not significant in oral
Discussion
The PD-1/PD-L1 blockade immunotherapy has recently renovated the therapeutic regimens in recurrent and metastatic HNSCC. To promote personalized treatment, robust biomarkers of treatment response are necessitated to guide patient selection. The PD-L1 expression assessed by IHC is the most common clinically used biomarker for treatment response. According to the current evidence in HNSCC [15], [16], [17], [52], patients with positive PD-L1 expression were indicated to have better responses or
Contributors
Yu-xiong Su designed the study, assisted in data inclusion and extraction, supervised the work of all contributors, and has primary responsibility for the study. Wei-fa Yang performed the study and contributed to the first draft. May CM Wong supervised the data analysis and contributed to data interpretation. Peter J Thomson helped data interpretation and discussion of results. Kai Yan Li did data analysis. All authors contributed to and approved final version of the manuscript.
Declaration of interests
We declare no competing interests.
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Acknowledgement
This study was funded by Hong Kong Research Grant Council General Research Fund (No. 17120718) and seed fund for basic research, the University of Hong Kong (No. 201511159130).
References (70)
- et al.
Telltale tumor infiltrating lymphocytes (TIL) in oral, head & neck cancer
Oral Oncol
(2016) - et al.
Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer
Immunity
(2013) - et al.
PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: a systematic review and meta-analysis
Crit Rev Oncol/Hematol
(2016) - et al.
Is pilocarpine effective in preventing radiation-induced xerostomia? A systematic review and meta-analysis
Int J Radiat Oncol Biol Phys
(2016) - et al.
Associations among pretreatment tumor necrosis and the expression of HIF-1alpha and PD-L1 in advanced oral squamous cell carcinoma and the prognostic impact thereof
Oral Oncol
(2015) - et al.
Relationship between the expressions of PD-L1 and tumor-infiltrating lymphocytes in oral squamous cell carcinoma
Oral Oncol
(2011) - et al.
Programmed cell death-ligand 1 expression in oral squamous cell carcinoma is associated with an inflammatory phenotype
Pathology
(2016) - et al.
Programmed death ligand-1 expression in non-small cell lung cancer
Lab Invest
(2014) - et al.
Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial
Lancet Oncol
(2016) - et al.
Cancer-cell-intrinsic mechanisms shaping the tumor immune landscape
Immunity
(2018)