PD-1 and PD-L1 expression on TILs in peritoneal metastases compared to ovarian tumor tissues and its associations with clinical outcome

Abstract

The therapeutic potential of immune checkpoint inhibitors is currently being investigated in epithelial ovarian cancer (EOC), but immunological effects of the programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis in EOC still remain poorly understood. The aim of this study was thus to compare infiltration rates of PD-1 and PD-L1 expressing tumor infiltrating leucocytes (TILs) in primary ovarian tumor tissue and metastatic intraperitoneal implants and to investigate its impact on overall survival (OS). Tumor specimens (ovarian tumor tissues and intraperitoneal metastases) of 111 patients were used to investigate the PD-1, PD-L1 and CD8 expression rates on TILs and PD-L1 expression rate of tumor cells. The percentages of CD8, PD-1, and PD-L1 expressing subpopulations of TILs differ in primary ovarian tumor tissues and metastatic intraperitoneal implants. High PD-1 among TILs in peritoneal metastases were associated with favorable OS. High PD-L1 expression in TILs was associated with poor OS. Combining both factors in peritoneal metastases revealed an unfavorable prognosis. Primary ovarian tumor tissue and intraperitoneal metastatic tissues in EOC might have different strategies to evade immune control. Those findings are of importance for the process of biomarker assessment to predict patients’ response to immunotherapy.

PD-L1 Expression on Circulating Tumour-Derived Microvesicles as a Complementary Tool for Stratification of High-Grade Serous Ovarian Cancer Patients

“…In analogy to TC-derived PD-L1 + MVs, we suggest that this disagreement can be explained by the release into the circulation of leuko-derived PD-L1 + MVs from tumour locales that were not sampled for IHC assay. Supporting this view, we found a heterogeneous PD-L1 expression on immune cells from different tumour locales by IHC, which is in accord with earlier studies [38,44]. An alternative, non-mutually exclusive explanation is that PD-L1 + immune cells from non-neoplastic tissues contributed to the global leuko-derived PD-L1 + MVs pool.…”

“…These results are not surprising; the divergent PD-L1 expressions in different tumour sites due to intrinsic tumour heterogeneity has already been highlighted in a variety of malignancies [21][22][23]. Similar observations have been reported in the OC setting; evaluation of PD-L1 expression in tumour biopsies falls short of reflecting the PD-L1 status of the entire tumour unless several lesions are scored [37,38]. The discordance rate of the estimated PD-L1 score between specimens from different tumour sites highlights the difficulty of representing PD-L1 status with a single test value and is relevant for clinical decision-making when anti-PD-L1/PD-1 blocking agents are a treatment option.…”

“…In analogy with earlier studies in different tumour settings [40,41], future studies aimed at optimising OC patient stratification for anti-PD-1/anti-PD-L1 treatments might benefit from measuring circulating TC-derived PD-L1 + MVs. Noteworthily, complementing PD-L1 assessment by IHC with quantification of plasma levels of PD-L1 + TC-derived MVs might also contribute to solve the still controversial issue of the prognostic significance of PD-L1 expression on TCs in OC patients-either high expression indicating poor prognosis [42,43], favourable prognosis [10,44,45], or irrelevancy [37,38].…”

Associations between DNA Damage and PD-L1 Expression in Ovarian Cancer, a Potential Biomarker for Clinical Response

“…These tumors also have a poorer response to conventional chemotherapy [ 47 ]. Mucinous ovarian tumors are rare, so specific responses of this class of tumors to PD-L1 blockade are still developing, but the high expression of PD-L1 and known increase in TILs make it an interesting target for immunotherapy [ 17 , 19 ]. High grade serous tumors also showed good correlation (r = 0.67) with PD-L1 expression.…”

“…PD-1/PD-L1 inhibitors are currently under investigation for use in ovarian cancer in multiple clinical trials [ 8 , 13 , 14 , 15 ]. Evidence suggests that PD-1/PD-L1 blockade success in ovarian cancer differs based on histological pathology [ 15 , 16 , 17 , 18 , 19 ]. Although these therapies show promise in some patients, responses are highly variable among ovarian tumors, and the cause of this variability is currently unknown [ 14 ].…”