Tumor rejection properties of gp100209-specific T cells correlate with T cell receptor binding affinity towards the wild type rather than anchor-modified antigen

Although there are exceptions and outliers, T cell functional responses generally correlate with the affinity of a TCR for a peptide/MHC complex. In one recently described outlier case, the most promising clinical candidate in a series of TCRs specific for the gp100(209) melanoma antigen bound with the weakest solution affinity and produced the least amount of cytokine in vitro. Hypotheses for this outlier behavior included unusual cytokine expression patterns arising from an atypical TCR binding geometry. Studying this instance in more detail, we found here that outlier behavior is attributable not to unusual cytokine patterns or TCR binding, but the use of a position 2 anchor-modified peptide variant in in vitro experiments instead of the wild type antigen that is present in vivo. Although the anchor-modified variant has been widely used in basic and clinical immunology as a surrogate for the wild type peptide, prior work has shown that TCRs can clearly distinguish between the two. We show that when this differential recognition is accounted for, the functional properties of gp100(209)-specific TCRs track with their affinity towards the peptide/MHC complex. Beyond demonstrating the correlates with T cell function for a clinically relevant TCR, our results provide important considerations for selection of TCRs for immunotherapy and the use of modified peptides in immunology.

Automated summary

T cell functional responses generally correlate with the TCR affinity for a peptide/MHC complex, but outliers exist. In a specific outlier case, the unusual behavior was attributed to the use of a position 2 anchor-modified peptide variant instead of the wild type antigen. This study highlights the importance of considering the differences between modified peptides and wild type antigens when selecting TCRs for immunotherapy.