Integrative analysis of T cell subset-specific ICOS expression and tumor HLA class I/II expression in lung adenocarcinoma: implications for their interaction and clinical outcome

Cancer Immunol Immunother. 2026 Feb 28;75(3):89. doi: 10.1007/s00262-026-04327-w.

Abstract

Objectives: Inducible T cell costimulator (ICOS) is a CD28-family costimulatory receptor with bidirectional therapeutic effects on antitumor immunity, and HLA-mediated tumor recognition is essential for effective T cell responses. However, their clinicopathological significance in lung adenocarcinoma (LUAD) is not fully understood. We investigated subset-specific pattern of ICOS expression and examined whether ICOS+ tumor-infiltrating lymphocyte (TIL) density and tumor HLA expression provide immune context and prognostic information in LUAD.

Materials and methods: We examined 228 resected LUADs by immunohistochemistry. ICOS+ TIL density and HLA class I and HLA-DR status were compared with the densities of CD8+, CD3+CD8-, and FOXP3+ TILs and with postsurgical outcomes. Subset-specific ICOS expression was evaluated using multiplex pseudocolored immunohistochemistry in 10 representative cases selected from the ICOS+ TIL-high group and validated using a publicly available single-cell RNA-seq dataset.

Results: ICOS+ TIL density correlated with each T cell subset. Multiplex analysis showed the highest ICOS positivity among Tregs, followed by CD4+ non-Tregs and CD8+ TILs. Because CD4+ non-Tregs were numerically predominant, ICOS+CD4+ non-Tregs constituted the largest ICOS+ fraction. Single-cell RNA-seq analysis corroborated these findings. ICOS+ TIL density was significantly higher in HLA-DR-strong tumors, and tumor HLA class I and HLA-DR were associated with longer recurrence-free survival. ICOS had no overall prognostic impact; however, among HLA-DR-strong tumors, ICOS-high patients tended toward longer cancer-specific survival.

Conclusion: In LUAD, ICOS+ TIL density largely reflects ICOS+CD4+ non-Treg infiltration and is enriched in HLA-DR-strong tumors. Tumor HLA expression was associated with favorable prognosis, and ICOS may have context-dependent clinical significance that warrants further investigation.

Keywords: CD278; HLA class I; HLA class II; Inducible T cell costimulator; Lung adenocarcinoma; Tumor-infiltrating lymphocyte.

MeSH terms

  • Adenocarcinoma of Lung* / immunology
  • Adenocarcinoma of Lung* / metabolism
  • Adenocarcinoma of Lung* / mortality
  • Adenocarcinoma of Lung* / pathology
  • Adult
  • Aged
  • Female
  • Histocompatibility Antigens Class I* / immunology
  • Histocompatibility Antigens Class I* / metabolism
  • Humans
  • Inducible T-Cell Co-Stimulator Protein* / immunology
  • Inducible T-Cell Co-Stimulator Protein* / metabolism
  • Lung Neoplasms* / immunology
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / mortality
  • Lung Neoplasms* / pathology
  • Lymphocytes, Tumor-Infiltrating* / immunology
  • Lymphocytes, Tumor-Infiltrating* / metabolism
  • Male
  • Middle Aged
  • Prognosis
  • T-Lymphocyte Subsets* / immunology
  • T-Lymphocyte Subsets* / metabolism

Substances

  • Inducible T-Cell Co-Stimulator Protein
  • ICOS protein, human
  • Histocompatibility Antigens Class I