Low-avidity T cells drive endogenous tumor immunity in mice and humans
Summit Singhaviranon, Joseph P. Dempsey, Adam T. Hagymasi, Ion Măndoiu, Pramod K. Srivastava
Abstract
T cells recognize neoepitope peptide-major histocompatibility complex class I on cancer cells. The strength (or avidity) of the T cell receptor–peptide-major histocompatibility complex class I interaction is a critical variable in immune control of cancers. Here, we analyze neoepitope-specific CD8 cells of distinct avidities and show that low-avidity T cells are the sole mediators of cancer control in mice and are solely responsive to checkpoint blockade in mice and humans. High-avidity T cells are ineffective and immune-suppressive. The mechanistic basis of these differences lies in the higher exhaustion status of high-avidity cells. High-avidity T cells have a distinct transcriptomic profile that is used here to calculate an ‘avidity score’, which we then use for in silico identification of low-avidity and high-avidity T cells in mice and humans. Surprisingly, CD8+ T cells with identical T cell receptors exhibit wide variation in avidities, suggesting an additional level of regulation of T cell activity. Aside from providing a better understanding of endogenous T cell responses to cancer, these findings might instruct future immunotherapy strategies. Here the authors show that, in mouse tumors, CD8+ T cells with a low-avidity TCR are the mediators of antitumor and immunotherapy responses, in part because T cells with a high-avidity TCR are more exhausted.