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.
Highlights
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
In a previous study we showed that the upregulation of PD-L1 on tumor cells is in an interplay with the down-regulation of tumor cell MHC I gene expression, highlighting several different immunological escape mechanisms in E OC9
In 111 EOC patients we found no significant correlations between the respective percentages of CD8, PD-1, and PD-L1 expressing tumor infiltrating leucocytes (TILs) in ovarian tumor tissues compared to intraperitoneal metastatic tissues obtained at primary debulking surgery
Summary
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. Treatment for epithelial ovarian cancer (EOC) has recently been improved for a subset of patients due to extensive research on homologous recombination deficiency and associated therapeutic targets Despite those achievements, EOC is mainly diagnosed at an advanced stage and recurrence rates as well as mortality are high and new therapeutic strategies are needed. The majority of tumors are diagnosed at an advanced stage with multiple intraperitoneal metastases, present as miliary or bulky lesions[7,8,9] and just alike, recurrence predominantly occurs within the intraperitoneal cavity It can be assumed, that the functional impairment of T-cell mediated immunity is special in ovarian cancer due to the complex microenvironment of the intraperitoneal ecosystem. Parameter Total number of patients enrolled Age at diagnosis (years) Histological type Serous adenocarcinoma LGSOC HGSOC Endometrioid adenocarcinoma Mucinous adenocarcinoma Clear cell carcinoma Tumor stage FIGO I FIGO II FIGO III FIGO IV Residual tumor (one case missing and imputed as R1) R1 (≥ 2 cm); R1 (Yes) R0 (< 2 cm); R0 (No) Source of tissue Primary tumors only Implants only Paired primary and implant
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