T-cell receptor affinity in the age of cancer immunotherapy

Abstract

The strength of the interaction between T-cell receptors (TCRs) and their ligands, peptide/major histocompatibility complex complexes (pMHCs), is one of the most frequently discussed and investigated features of T cells in immuno-oncology today. Although there are many molecules on the surface of T cells that interact with ligands on other cells, the TCR/pMHC is the only receptor-ligand pair that offers antigen specificity and dictates the functional response of the T cell. The strength of the TCR/pMHC interaction, along with the environment in which this interaction takes place, is key to how the T cell will respond. The TCR repertoire of T cells that interact with tumor-associated antigens is vast, although typically of low affinity. Here, we focus on the low-affinity interactions between TCRs from CD8+ T cells and different models used in immuno-oncology.

Keywords: CD8+ T cells; TCR-pMHC affinity; altered peptide ligands; low affinity; tumor antigens.

Figure 1.

Average T cell receptor binding affinities to differing types of antigen-MHC complexes in the thymus and periphery. Self antigen, TAA, and positive selection are considered low-affinity TCR-pMHC interactions.

Figure 2.

Functional differences in CD8+ T cells between low- and high-affinity TCR-pMHC interactions. Relative to high-affinity T cells, low-affinity T cells play a distinct role in development, effector function, memory function and in the tumor microenvironment. Both are crucial contributors to the immune response.