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

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. 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. 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. 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.