Tumor-specific exhausted CD8 T cells (Tex) adopt diverse phenotypes across human cancers, but the drivers of this heterogeneity remain poorly understood. Using flow cytometry and single-cell RNA and T cell receptor (TCR) sequencing of 106,667 tumor-infiltrating CD8 T cells from head and neck squamous cell carcinoma (HNSCC) tumors, we identified and validated three Tex subsets, each with distinct clonotypes: (1) Tex-Conv, expressing conventional exhaustion genes; (2) Tex-CCR6, distinguished by CCR6 and Tc17-like genes; and (3) Tex-KLR, marked by killer cell lectin-like receptors (KLRs) and particularly high immune checkpoint expression. Through multiplexed immunofluorescence, we found that Tex-KLR cells preferentially localized within tumor nests in direct contact with malignant cells. Due to the elevated checkpoint expression, unique clonotypes, and intra-tumoral localization of Tex-KLR cells, we hypothesized that high-avidity TCR signaling induces this state. We therefore developed an in vitro co-culture system to model TCR avidity in primary human CD8 T cells and identified high-avidity, NFAT-dependent TCR signaling as a key driver of the Tex-KLR signature. Strikingly, in HNSCC and breast cancer patients, we found that Tex-KLR cells are associated with response to neoadjuvant anti-PD-1 therapy. Together, our findings demonstrate that high-avidity, NFAT-dependent TCR signaling shapes Tex phenotypes and promotes the Tex-KLR signature. These data support further investigation of the Tex-KLR subtype and its role, dynamics, and targetable translational applications to cancer immunotherapy.
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