Cancer Immunol Res. 2026 Jun 8. doi: 10.1158/2326-6066.CIR-25-1109. Online ahead of print.
ABSTRACT
Immune checkpoint inhibitors (ICIs) have improved clear-cell renal cell carcinoma (ccRCC) therapy, yet many patients remain unresponsive. Alternative strategies are needed, and the HLA-G/ILT2 axis has emerged as a promising immunosuppressive pathway. Here, we deeply characterized CD8⁺ILT2⁺ tumor-infiltrating lymphocytes (TILs) as a distinct subset from CD8⁺PD1⁺ TILs in ccRCC, using high-dimensional spectral flow cytometry, single-cell transcriptomics, and TCR clonotype analysis. CD8⁺ILT2⁺ TILs were terminally differentiated, highly cytotoxic “bystander” cells, enriched for virus-specific TCRs. They phenotypically, transcriptionally and functionally mirrored their circulating counterparts, suggesting peripheral recruitment. In dynamic co-culture assays, they exhibited potent TCR-independent cytotoxicity, mediated by activating innate receptors, namely NKG2D. However, HLA-G inhibited this activity, underscoring the immune-evasive role of the HLA-G/ILT2 axis. Our study defines CD8⁺ILT2⁺ TILs as an untapped effector population with potential antitumor activity and a promising therapeutic target in ccRCC. These findings offer new insights into TIL functional diversity and pave the way for innovative immunotherapies beyond conventional ICIs.
PMID:42258315 | DOI:10.1158/2326-6066.CIR-25-1109