PD-L1 on Tumor Cells Is Induced in Ascites and Promotes Peritoneal Dissemination of Ovarian Cancer through CTL Dysfunction

Abstract

Purpose: Ovarian cancer often progresses by disseminating to the peritoneal cavity, but how the tumor cells evade host immunity during this process is poorly understood. Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be expressed in cancer cells. The purpose of this study is to elucidate the function of PD-L1 in peritoneal dissemination.Experimental Design: Ovarian cancer cases were studied by microarray and immunohistochemistry. PD-L1 expression in mouse ovarian cancer cell line in various conditions was assessed by flow cytometry. PD-L1-overexpression cell line and PD-L1-depleted cell line were generated, and cytolysis by CTLs was analyzed, and alterations in CTLs were studied by means of timelapse and microarray. These cell lines were injected intraperitoneally to syngeneic immunocompetent mice.Results: Microarray and immunohistochemistry in human ovarian cancer revealed significant correlation between PD-L1 expression and peritoneal positive cytology. PD-L1 expression in mouse ovarian cancer cells was induced upon encountering lymphocytes in the course of peritoneal spread in vivo and coculture with lymphocytes in vitro. Tumor cell lysis by CTLs was attenuated when PD-L1 was overexpressed and promoted when it was silenced. PD-L1 overexpression inhibited gathering and degranulation of CTLs. Gene expression profile of CTLs caused by PD-L1-overexpressing ovarian cancer was associated with CTLs exhaustion. In mouse models, PD-L1 depletion resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival.Conclusion: PD-L1 expression in tumor cell promotes peritoneal dissemination by repressing CTL function. PD-L1-targeted therapy is a promising strategy for preventing and treating peritoneal dissemination.

PD-1 and CD103 Are Widely Coexpressed on Prognostically Favorable Intraepithelial CD8 T Cells in Human Ovarian Cancer

“…In support of this notion, prior studies have shown that NY-ESO-1-specific CD8 þ TIL from ovarian cancer patients frequently express PD-1 and are functionally impaired compared with their counterparts in peripheral blood (20). Moreover, ovarian tumor cells have been reported to express high levels of PD-L1 (21,22).…”

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

“…Modulation of PD-L1 expression may impact the fate of tumor cells and infiltrating immune cells from the microenvironment in adenocarcinomas. [68][69][70][71] After CD39 blockade or IL-27 depletion, the reduced PD-L1 expression by macrophages might affect the ratio of costimulatory vs. coinhibitory molecules in the context of inflammation.…”

Malignant Pleural Effusion and ascites Induce Epithelial-Mesenchymal Transition and Cancer Stem-like Cell Properties via the Vascular Endothelial Growth Factor (VEGF)/Phosphatidylinositol 3-Kinase (PI3K)/Akt/Mechanistic Target of Rapamycin (mTOR) Pathway

“…Besides, given that different immune cell populations are present in malignant PE/ascites, we also focused on the cytotoxicity of immune cells on cancer cells cultured with malignant exudates. Previous studies have shown that malignant PE/ascites foster immune privilege and facilitate tumor cell survival (39,40). One of these reports shows that tumor cells in the peritoneal cavity express PD-L1 and escape from CD8ϩ cytotoxic lymphocytes (40).…”