ILT2 identifies an unexploited pool of intratumoral CD8+ bystander T cells with TCR-independent cytotoxicity in renal cell carcinoma
(1) Laboureur R (2) Dumont C (3) Koca D (4) Lugand L (5) Bossis M (6) Artru E (7) Jacquier A (8) Verine J (9) Bouhidel F (10) Djouadou M (11) Masson-Lecomte A (12) Russick J (13) Carosella ED (14) Desgrandchamps F (15) Guyon L (16) Tonnerre P (17) LeMaoult J (18) Rouas-Freiss N
Analyzing primary ccRCC samples, Laboureur et al. identified a subset of CD8+ILT2+PD-1- TILs that were terminally differentiated and expressed high baseline levels of granzyme B, perforin, and NKG2D, but lacked tumor specificity and tissue residency markers. These “bystander” T cells, likely recruited from the periphery, exhibited CD3-driven activation and IFNγ production in response to viral antigens, as well as IL-15/NKG2D-driven, TCR-independent cytotoxicity. The innate-like cytotoxicity was inhibited by HLA-G (an ILT2 ligand expressed on tumor cells), suggestive of a checkpoint axis that could potentially be targeted for immunotherapy.
Contributed by Lauren Hitchings
(1) Laboureur R (2) Dumont C (3) Koca D (4) Lugand L (5) Bossis M (6) Artru E (7) Jacquier A (8) Verine J (9) Bouhidel F (10) Djouadou M (11) Masson-Lecomte A (12) Russick J (13) Carosella ED (14) Desgrandchamps F (15) Guyon L (16) Tonnerre P (17) LeMaoult J (18) Rouas-Freiss N
Analyzing primary ccRCC samples, Laboureur et al. identified a subset of CD8+ILT2+PD-1- TILs that were terminally differentiated and expressed high baseline levels of granzyme B, perforin, and NKG2D, but lacked tumor specificity and tissue residency markers. These “bystander” T cells, likely recruited from the periphery, exhibited CD3-driven activation and IFNγ production in response to viral antigens, as well as IL-15/NKG2D-driven, TCR-independent cytotoxicity. The innate-like cytotoxicity was inhibited by HLA-G (an ILT2 ligand expressed on tumor cells), suggestive of a checkpoint axis that could potentially be targeted for immunotherapy.
Contributed by Lauren Hitchings
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.
Author Info:
(1) CEA Fontenay-aux-Roses Paris France. ROR: https://ror.org/010j2gw05 (2) Hpital Saint-Louis Paris France. ROR: https://ror.org/049am9t04 (3) CEA Grenoble Grenoble France. ROR:
https://ror.org/02mg6n827 (4) CEA Fontenay-aux-Roses Paris France. ROR: https://ror.org/010j2gw05 (5) Inserm Paris France. ROR: https://ror.org/02vjkv261 (6) Inserm Paris France. ROR: https://ror.org/02vjkv261 (7) CEA Fontenay-aux-Roses Paris France. ROR: https://ror.org/010j2gw05 (8) APHP Paris France. (9) Hpital Saint-Louis, Assistance publique Hpitaux de Paris Paris France. (10) APHP Paris France. (11) Assistance Publique - Hpitaux de Paris Paris France. ROR: https://ror.org/00pg5jh14 (12) CEA Paris-Saclay - Etablissement de Fontenay-aux-roses Paris France. (13) Commissariat l'Energie Atomique et aux Energies Alternatives Paris France. (14) AP-HP, Hpital Saint-Louis Paris France. (15) Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA) Grenoble France. (16) Inserm Paris France. ROR: https://ror.org/02vjkv261 (17) CEA Fontenay-aux-Roses Paris France. ROR: https://ror.org/010j2gw05 (18) Atomic Energy and Alternative Energies Commission Paris France. ROR: https://ror.org/00jjx8s55
Citation: Cancer Immunol Res 2026 Jun 8 Epub06/08/2026
