Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer

Gastric Cancer. 2016 Jan;19(1):42-52. doi: 10.1007/s10120-014-0440-5. Epub 2014 Nov 26.

Abstract

Background: There are few data on the clinical implications of immunosuppressive protein expression in tumors and immune cell infiltration within the tumor microenvironment in patients with gastric cancer (GC).

Methods: In this study, 243 patients with curatively resected GC were included. The levels of immunosuppressive protein expression [programmed cell death 1 ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), and indoleamine 2,3-dioxygenase (IDO)] in tumors and the densities of immune cells [CD3(+), CD4(+), CD8(+), or PD-1(+) cells] within the tumor microenvironment were measured using immunohistochemical analysis.

Results: Positive PD-L1, CTLA-4, and IDO expression was observed in 43.6, 65.8, and 47.7% of the patients, respectively. Expression of PD-L1, CTLA-4, and IDO was related to less advanced stage, intestinal type, and well/moderately differentiated adenocarcinoma (P < 0.05). PD-L1 expression was related to better disease-free survival (DFS) and overall survival (OS) in GC [PD-L1(+) vs. PD-L1(-) tumors: 5-year DFS rate, 82.6 vs. 66.9%; 5-year OS rate, 83.0 vs. 69.1% (P values <0.05)]. Survival outcomes were also better in patients with a higher density of CD3(+) cells within the tumor microenvironment than in those with a lower density of CD3(+) cells [5-year DFS rate, 80.9 vs. 67.0%; 5-year OS rate, 82.5 vs. 68.0% (P values <0.05)]. In multivariate analysis, these two immune markers had a prognostic impact on survival, independent of other clinical variables.

Conclusions: GC patients with immunosuppressive protein expression (PD-L1, CTLA-4, or IDO) had distinct clinicopathological characteristics. PD-L1(+) expression and a high-CD3 tumor microenvironment are favorable prognostic markers in GC.

Keywords: CD3; Gastric cancer; PD-1; PD-L1; Tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism
  • Biomarkers, Tumor / immunology
  • CD3 Complex / metabolism
  • CTLA-4 Antigen / immunology
  • CTLA-4 Antigen / metabolism
  • Disease-Free Survival
  • Female
  • Humans
  • Immune Tolerance / immunology
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Male
  • Middle Aged
  • Prognosis
  • Stomach Neoplasms / immunology*
  • Stomach Neoplasms / mortality*
  • Stomach Neoplasms / pathology
  • Stomach Neoplasms / surgery
  • Tumor Microenvironment / immunology*

Substances

  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • CD3 Complex
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • indoleamine 2,3-dioxygenase 1, human