Using scRNAseq, TCRseq, flow cytometry, and high-throughput peptide screens, Lu et al. characterized T cells in resected tumors and blood from patients with melanoma, and identified a subpopulation of tumor antigen-specific KIR+CD8+ Tregs. Circulating KIR+CD8+ Tregs in patients with melanoma were conserved across blood and tumor compartments, expressed inhibitory and cytotoxic markers, and specifically targeted and lysed other tumor peptide-reactive CD8+ T cells, contributing to immune evasion. The frequencies of circulating KIR+CD8+ Tregs correlated with poor overall survival in patients with melanoma.
Contributed by Shishir Pant
ABSTRACT: 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(+) T cells and implicate KIR(+)CD8(+) regulatory T cells as a cellular mediator of immune evasion in human cancer.
Author Info: (1) Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, CT, USA. Benjamin.Lu@yale.edu. Department of Neurology, Yale School of Medicine, New Haven, CT, U
Author Info: (1) Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, CT, USA. Benjamin.Lu@yale.edu. Department of Neurology, Yale School of Medicine, New Haven, CT, USA. Benjamin.Lu@yale.edu. (2) Department of Neurology, Yale School of Medicine, New Haven, CT, USA. University of Toulouse, Inserm, CNRS, University Toulouse III-Paul Sabatier, Cancer Research Center of Toulouse, Toulouse, France. (3) Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA. Department of Pathology, Yale School of Medicine, New Haven, CT, USA. (4) Applied Mathematics Program, Yale University, New Haven, CT, USA. (5) Repertoire Immune Medicines, Cambridge, MA, USA. (6) Repertoire Immune Medicines, Schlieren, Switzerland. (7) Repertoire Immune Medicines, Cambridge, MA, USA. (8) Department of Neurology, Yale School of Medicine, New Haven, CT, USA. University of Toulouse, Inserm, CNRS, University Toulouse III-Paul Sabatier, Cancer Research Center of Toulouse, Toulouse, France. (9) Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. (10) Department of Neurology, Yale School of Medicine, New Haven, CT, USA. (11) Department of Neurology, Yale School of Medicine, New Haven, CT, USA. (12) Department of Genetics, Yale School of Medicine, New Haven, CT, USA. (13) Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, CT, USA. (14) Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, CT, USA. (15) Department of Dermatology, Yale School of Medicine, New Haven, CT, USA. (16) Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, CT, USA. (17) Department of Neurology, Yale School of Medicine, New Haven, CT, USA. (18) Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA. (19) Department of Surgery, Yale School of Medicine, New Haven, CT, USA. (20) Department of Surgery, Yale School of Medicine, New Haven, CT, USA. (21) Department of Dermatology, Yale School of Medicine, New Haven, CT, USA. (22) Department of Pathology, Yale School of Medicine, New Haven, CT, USA. Applied Mathematics Program, Yale University, New Haven, CT, USA. (23) Repertoire Immune Medicines, Cambridge, MA, USA. (24) Repertoire Immune Medicines, Schlieren, Switzerland. (25) Repertoire Immune Medicines, Schlieren, Switzerland. (26) Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, CT, USA. (27) Department of Neurology, Yale School of Medicine, New Haven, CT, USA. David.Hafler@yale.edu. Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. David.Hafler@yale.edu. Broad Institute of MIT and Harvard University, Cambridge, MA, USA. David.Hafler@yale.edu.
