A Self-reactive Innate-like T-cell Program Was Identified in Cancer Immunity

Despite the clinical success of immune checkpoint blockade (ICB) therapy, many patients still do not respond even with the induction of cancer immunity, suggesting the need for further investigation into the role other classes of infiltrating T cells play in cancer immunosurveillance. Chou, Zhang, and colleagues sought to explore this topic by examining the heterogeneity of tumor-infiltrating T cells using single-cell RNA sequencing technology. Five clusters were identified, with each showing diverse differentiation and proliferation states. One cluster featured cells with a specific gene signature defined as αβ T-cell receptor lineage innate-like T cells with high cytotoxic potential (αβILTCK), which were observed across multiple tumor types, supporting this differentiation program being an evolutionarily conserved tumor-elicited immune response. Interrogation into the differences between this cluster and conventional PD-1⁺ T cells revealed the ability of αβILTCKs to react to heterologous cancer cells, suggesting their recognition of unmutated antigens shared between cancer cells even between different experimental mice. Moreover, studies showed that αβILTCKs were restricted to specific peptide-classical major histocompatibility complex I expression and are independent of dendritic cell–mediated priming. Furthermore, αβILTCKs and PD-1⁺ T cells were indicated as being two mutually exclusive cell-fate choices with commitment to the lineage occurring during thymocyte development. Specifically, the αβILTCK lineage commitment was driven by strong autoreactivity with this αβILTCK intratumoral compartment being replenished by thymic progenitors. Comparison of the αβILTCKs and PD-1⁺ T cells showed that Fcer1g was differentially expressed and was a defining marker for the αβILTCK lineage regardless of their activation state, with FCER1G⁺ cells being enriched in tumor tissues relative to adjacent normal in patients with colon cancer. Additionally, deletion of IL15 in murine tumor cells reduced αβILTCKs infiltrating into the tumor, with these mice also exhibiting enhanced tumor growth. In summary, this study reveals FCER1G⁺ αβILTCKs as a conserved class of tumor-specific T cells with IL15 being necessary for their antitumor effects and suggests targeting this population in tumors with low mutational burden or those that are refractory to ICB.

Chou C, Zhang X, Krishna C, Nixon BG, Dadi S, Capistrano KJ, et al. Programme of self-reactive innate-like T cell-mediated cancer immunity. Nature 2022;605:139–45.

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