Researchers led by Ludwig Lausanne’s Alexandre Harari reported in Nature Communications in June their exploration of why T cells that target neoantigens, which are generated by random mutations in cancer cells, are typically associated with better anti-tumor T cell responses. Alexandre and his colleagues profiled the biophysical and chemical properties of the T cell receptors (TCRs) of a large library of CD8+ T cells isolated from tumors and the blood stream of cancer patients, including those specific to cancer antigens, viral antigens and neoantigens. They discovered that neoantigen-targeting TCRs tend to have greater structural and functional avidity than those that target other types of cancer antigens; that is, they are both more sensitive in detecting and persistent in binding target antigens presented to them in complex with MHC molecules. T cells endowed with such TCRs tend to express a gene, CXCR3, associated with T cell homing and are far more likely to find and take up residence in tumors after adoptive cell therapy. The researchers also identified specific structural and chemical properties shared by high-avidity TCRs and applied these insights to develop and validate—using T cells isolated from tumors—a computational model to predict TCR avidity. Their findings provide a rational method for the selection of T cells to improve personalized immunotherapies.
Neoantigen-specific CD8 T cells with high structural avidity preferentially reside in and eliminate tumors
Nature Communications, 2023 June 6