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

Cancer Sci. 2020 Aug;111(8):3057-3070. doi: 10.1111/cas.14514. Epub 2020 Jul 9.

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.

Keywords: HLA class I antigens; HLA-E; HLA-G; IFNγ; pancreatic cancer.

Publication types

  • Observational Study

MeSH terms

  • Aged
  • B7-H1 Antigen / metabolism
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / mortality*
  • Carcinoma, Pancreatic Ductal / pathology
  • Carcinoma, Pancreatic Ductal / surgery
  • Disease-Free Survival
  • Female
  • Gene Expression Regulation, Neoplastic / immunology
  • HLA-G Antigens / analysis
  • HLA-G Antigens / immunology
  • HLA-G Antigens / metabolism*
  • Histocompatibility Antigens Class I / analysis
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Immunohistochemistry
  • Interferon-gamma / metabolism
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Pancreas / pathology
  • Pancreas / surgery
  • Pancreatectomy
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / mortality*
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / surgery
  • Prognosis
  • Programmed Cell Death 1 Ligand 2 Protein / metabolism
  • Programmed Cell Death 1 Receptor / metabolism
  • Tumor Escape*
  • Tumor Microenvironment / immunology

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • HLA-E antigen
  • HLA-G Antigens
  • Histocompatibility Antigens Class I
  • IFNG protein, human
  • PDCD1 protein, human
  • PDCD1LG2 protein, human
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • Interferon-gamma