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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.

αβ T cell antigen receptors (TCRs) bind complexes of peptide and major histocompatibility complex (pMHC) with low affinity, which poses a considerable challenge for the direct identification of αβ T cell cognate peptides. Here we describe a platform for the discovery of MHC class II epitopes based on the screening of engineered reporter cells expressing novel pMHC–TCR (MCR) hybrid molecules carrying cDNA-derived peptides. This technology identifies natural epitopes of CD4+T cells in an unbiased and efficient manner and allows detailed analysis of TCR cross-reactivity that provides recognition patterns beyond discrete peptides. We determine the cognate peptides of virus- and tumor-specific T cells in mouse disease models and present a proof of concept for human T cells. Furthermore, we use MCR to identify immunogenic tumor neo-antigens and show that vaccination with a peptide naturally recognized by tumor-infiltrating lymphocytes efficiently protects mice from tumor challenge. Thus, the MCR technology holds promise for basic research and clinical applications, allowing the personalized identification of T cell–specific neo-antigens in patients.

In the version of this article initially published, a reference (23) was cited incorrectly and two references were not included in the second sentence of the first paragraph of the second Results subsection (‘Screening for gp61 mimotopes with different functional properties’). The correct citation is as follows: “... we replaced the very stable GFP with a slow fluorescent timer (FT)27,28.” Full details on the added references can be found in the correction notice. The errors have been corrected in the print, PDF and HTML versions of the paper.