TCR affinity for p/MHC formed by tumor antigens that are self-proteins: impact on efficacy and toxicity

Abstract

Recent studies have shown that the range of affinities of T cell receptors (TCRs) against non-mutated cancer peptide/class I complexes are lower than TCR affinities for foreign antigens. Raising the affinity of TCRs for optimal activity of CD8 T cells, and for recruitment of CD4 T cell activity against a class I antigen, provides opportunities for more robust adoptive T cell therapies. However, TCRs with enhanced affinities also risk increased reactivity with structurally related self-peptides, and off-target toxicities. Careful selection of tumor peptide antigens, in silico proteome screens, and in vitro peptide specificity assays will be important in the development of the most effective, safe TCR-based adoptive therapies.

Figure 1. Relationship between TCR affinity and T cell activity for CD8 and CD4 T cells

TCR affinity for class I pep/MHC impacts T cell activity for CD8 (top) and CD4 (bottom) T cells. CD8 T cells are more sensitive at weaker affinities, due to the contribution of the CD8 co-receptor to class I MHC binding, regardless of bound peptide. At higher affinity ranges, peptides that are structurally similar to the cognate peptide (tumor antigen in the present review) are capable of functionally cross-reacting with the T cell.

Figure 2. Conserved TCR docking onto pepMHC

CDR loops of the DMF5 TCR (PDB ID=3QDG) are shown binding to MART1/HLA-A2 as an example of the highly conserved docking geometry observed between TCRs and MHCs. HLA-A2 is shown in gray; MART1 peptide is shown in yellow. CDR3 loops (CDR3α in red, CDR3β in brick red) dock predominately over peptide, while CDR2 loops (CDR2α in green, CDR3β in lime green) predominately contact MHC. CDR1 loops (CDR1α in blue, CDR1β in navy) can contact both the MHC and the peptide; the CDR1α loop in particular frequently makes specific contacts with the N-terminus of the peptide.