biostudies-literatureLu BYU.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)U.S. Department of Health & Human Services | NIH | U.S. National Library of MedicineNIAID NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious DiseasesU.S. Department of Health & Human Services | NIH | National Cancer InstituteU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)NHGRI NIH HHSNCI NIH HHSNLM NIH HHSNIH HHS82-91https://www.ebi.ac.uk/biostudies/studies/S-EPMC12285569biostudies-literatureUnknown26(1)Effective anti-tumor immunity is driven by cytotoxic CD8⁺ T cells with specificity for tumor antigens. However, the factors that control successful tumor rejection are not well understood. Here we identify a subpopulation of CD8⁺ T cells that are tumor-antigen-specific and can be identified by KIR expression but paradoxically impair anti-tumor immunity in patients with melanoma. These tumor-antigen-specific KIR⁺CD8⁺ regulatory T cells target other tumor-antigen-specific CD8⁺ T cells, can be detected in both the tumor and the blood, have a conserved transcriptional program and are associated with a poor overall survival. These findings broaden our understanding of the transcriptional and functional heterogeneity of human CD8⁺Nature immunologyCirculating tumor-reactive KIR<sup>+</sup>CD8<sup>+</sup> T cells suppress anti-tumor immunity in patients with melanoma.PMC12285569S10 OD030363R01 CA269286K12 CA215510R01 CA121974T32 CA233414U24 AI11867P30 CA016359UM1 HG009390T15 LM007056P50 CA121974R01 CA227473K12 CA215110P01 AI039671R01 AI22220Lucca LELu BYRayon-Estrada VHafler DAWei WZhang LWang JPham GHAizenbud LBacchiocchi AKojima MLObermair FJNogueira CVClune JChiang VKluger YHeer SAxisa PPKisielow JBuitrago-Pocasangre NCOlino KLewis WKluger HMHalaban RWalewski JJCoyle AJReeves SMfalseCirculating tumor-reactive KIR<sup>+</sup>CD8<sup>+</sup> T cells suppress anti-tumor immunity in patients with melanoma.Effective anti-tumor immunity is driven by cytotoxic CD8⁺ T cells with specificity for tumor antigens. However, the factors that control successful tumor rejection are not well understood. Here we identify a subpopulation of CD8⁺ T cells that are tumor-antigen-specific and can be identified by KIR expression but paradoxically impair anti-tumor immunity in patients with melanoma. These tumor-antigen-specific KIR⁺CD8⁺ regulatory T cells target other tumor-antigen-specific CD8⁺ T cells, can be detected in both the tumor and the blood, have a conserved transcriptional program and are associated with a poor overall survival. These findings broaden our understanding of the transcriptional and functional heterogeneity of human CD8⁺2025-01-01T00:00:00Z2025 Jan2026-03-15T17:56:06.85Z2025-08-13T03:04:39.833ZS-EPMC122855693960962610.1038/s41590-024-02023-4