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.
Cancer immunology research. 2026 Jun 08 [Epub ahead of print]
Rebecca Laboureur, Clément Dumont, Dzenis Koca, Leonard Lugand, Margaux Bossis, Emilie Artru, Alix Jacquier, Jerome Verine, Fatiha Bouhidel, Malika Djouadou, Alexandra Masson-Lecomte, Jules Russick, Edgardo D Carosella, François Desgrandchamps, Laurent Guyon, Pierre Tonnerre, Joel LeMaoult, Nathalie Rouas-Freiss
CEA Fontenay-aux-Roses Paris France., Hôpital Saint-Louis Paris France., CEA Grenoble Grenoble France., Inserm Paris France., APHP Paris France., Hôpital Saint-Louis, Assistance publique Hôpitaux de Paris Paris France., Assistance Publique - Hôpitaux de Paris Paris France., CEA Paris-Saclay - Etablissement de Fontenay-aux-roses Paris France., Commissariat à l'Energie Atomique et aux Energies Alternatives Paris France., AP-HP, Hôpital Saint-Louis Paris France., Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA) Grenoble France., Atomic Energy and Alternative Energies Commission Paris France.