title: PD-L1 on tumor cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer through CTL dysfunction.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Kaoru
authors: K
authors: Abiko
authors: Masaki
authors: M
authors: Mandai
authors: Junzo
authors: J
authors: Hamanishi
authors: Yumiko
authors: Y
authors: Yoshioka
authors: Noriomi
authors: N
authors: Matsumura
authors: Tsukasa
authors: T
authors: Baba
authors: Ken
authors: K
authors: Yamaguchi
authors: Ryusuke
authors: R
authors: Murakami
authors: Ayaka
authors: A
authors: Yamamoto
authors: Budiman
authors: B
authors: Kharma
authors: Kenzo
authors: K
authors: Kosaka
authors: Ikuo
authors: I
authors: Konishi
mesh_terms: D000818:Animals; D001201:Ascites / Q000235:genetics / Q000473:pathology; D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010529:Peritoneal Cavity / Q000473:pathology*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism* / Q000473:pathology
chemical_list: D060890:B7-H1 Antigen