Singhaviranon et al. analyzed neoepitope-specific CD8+ T cells of distinct avidities among TILs and LNs of two mouse cancers with different haplotypes and histologies. Only low-avidity T cells mediated tumor control and response to ICB, whereas high-avidity T cells were ineffective and immunosuppressive. Mechanistically, high-avidity T cells had a distinct transcriptomic profile and expressed higher levels of exhaustion markers. In silico, an avidity score identified low- and high-avidity T cells in mice and humans, and in human TILs, low-avidity TILs predicted ICB responses. The study also revealed unexpected diversity of avidities among single clonotypes in vivo.
Contributed by Katherine Turner
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.
Author Info: (1) Department of Immunology and Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT, USA. (2) Department of Immunology and Neag Comprehe
Author Info: (1) Department of Immunology and Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT, USA. (2) Department of Immunology and Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT, USA. (3) Department of Immunology and Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT, USA. (4) Department of Computer Science and Engineering, University of Connecticut Mansfield, CT, USA. (5) Department of Immunology and Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT, USA. Srivastava@uchc.edu.
