Assessing T Cell Receptor Affinity and Avidity Against Tumor Antigens

Cytotoxic CD8 T cells play an important role in protective immune responses. Through their T cell receptors (TCRs), they recognize antigenic peptides presented by MHC molecules (pMHC) at the surface of infected or malignant cells. Efficient triggering of T cell responses critically depends on the strength of TCR binding to cognate pMHC, i.e., the TCR-pMHC binding avidity. Stronger interactions confer superior T cell activation and protection from disease. This is of particular importance for the self/tumor antigen-specific T cell repertoire, which mostly relies on TCRs of intermediate to low avidity, due to central and peripheral tolerance mechanisms removing the high-avidity self-reactive T cells. Consequently, improving the efficacy of tumor-reactive T cells by enhancing their TCR-pMHC affinity has shown robust clinical antitumor responses. However, increasing TCR-pMHC binding avidity was also associated with on-target and off-target toxicities, as reviewed here. In parallel, numerous strategies have been developed with the aim to assess TCR-pMHC binding and kinetic interactions and identify the functionally most relevant T cells in the context of natural tumor antigen-specific CD8 T cell responses. We will discuss them as well as review latest technologies, which will likely offer in the near future increased clinical benefit for use in adoptive T cell therapies for cancer patients.