Neoantigen-specific CD8 T cells with high structural avidity preferentially reside in and eliminate tumors

The success of cancer immunotherapy depends in part on the strength of antigen recognition by T cells. Here, we characterize the T cell receptor (TCR) functional (antigen sensitivity) and structural (monomeric pMHC-TCR off-rates) avidities of 371 CD8 T cell clones specific for neoantigens, tumor-associated antigens (TAAs) or viral antigens isolated from tumors or blood of patients and healthy donors. T cells from tumors exhibit stronger functional and structural avidity than their blood counterparts. Relative to TAA, neoantigen-specific T cells are of higher structural avidity and, consistently, are preferentially detected in tumors. Effective tumor infiltration in mice models is associated with high structural avidity and CXCR3 expression. Based on TCR biophysicochemical properties, we derive and apply an in silico model predicting TCR structural avidity and validate the enrichment in high avidity T cells in patients' tumors. These observations indicate a direct relationship between neoantigen recognition, T cell functionality and tumor infiltration. These results delineate a rational approach to identify potent T cells for personalized cancer immunotherapy.

Automated summary

This study explores the functional and structural avidities of T cell clones specific for different antigens and finds that T cells from tumors have stronger functional and structural avidities compared to those from blood. Neoantigen-specific T cells have higher structural avidity and are preferentially detected in tumors. Based on these findings, the researchers develop an in silico model to predict TCR structural avidity and validate the enrichment of high avidity T cells in patients' tumors.