Expression of classical human leukocyte antigen class I antigens, HLA-E and HLA-G, is adversely prognostic in pancreatic cancer patients

Nobuyoshi Hiraoka, Yoshinori Ino, Shutaro Hori, Rie Yamazaki-Itoh, Chie Naito, Mari Shimasaki, Minoru Esaki, Satoshi Nara, Yoji Kishi, Kazuaki Shimada, Naoya Nakamura, Toshihiko Torigoe, Yuji Heike

Research output: Contribution to journalArticle

Abstract

The expression of classical human leukocyte antigen class I antigens (HLA-I) on the surfaces of cancer cells allows cytotoxic T cells to recognize and eliminate these cells. Reduction or loss of HLA-I is a mechanism of escape from antitumor immunity. The present study aimed to investigate the clinicopathological impacts of HLA-I and non–classical HLA-I antigens expressed on pancreatic ductal adenocarcinoma (PDAC) cells. We performed immunohistochemistry to detect expression of HLA-I antigens in PDAC using 243 PDAC cases and examined their clinicopathological influences. We also investigated the expression of immune-related genes to characterize PDAC tumor microenvironments. Lower expression of HLA-I, found in 33% of PDAC cases, was significantly associated with longer overall survival. Higher expression of both HLA-E and HLA-G was significantly associated with shorter survival. Multivariate analyses revealed that higher expression of these three HLA-I antigens was significantly correlated with shorter survival. Higher HLA-I expression on PDAC cells was significantly correlated with higher expression of IFNG, which also correlated with PD1, PD-L1 and PD-L2 expression. In vitro assay revealed that interferon gamma (IFNγ) stimulation increased surface expression of HLA-I in three PDAC cell lines. It also upregulated surface expression of HLA-E, HLA-G and immune checkpoint molecules, including PD-L1 and PD-L2. These results suggest that the higher expression of HLA-I, HLA-E and HLA-G on PDAC cells is an unfavorable prognosticator. It is possible that IFNγ promotes a tolerant microenvironment by inducing immune checkpoint molecules in PDAC tissues with higher HLA-I expression on PDAC cells.

Original languageEnglish
Pages (from-to)3057-3070
Number of pages14
JournalCancer science
Volume111
Issue number8
DOIs
Publication statusPublished - 2020 Aug 1

Keywords

  • HLA class I antigens
  • HLA-E
  • HLA-G
  • IFNγ
  • pancreatic cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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