Different affinity windows for virus and cancer-specific T-cell receptors: implications for therapeutic strategies

Abstract

T-cell destiny during thymic selection depends on the affinity of the TCR for autologous peptide ligands presented in the context of MHC molecules. This is a delicately balanced process; robust binding leads to negative selection, yet some affinity for the antigen complex is required for positive selection. All TCRs of the resulting repertoire thus have some intrinsic affinity for an MHC type presenting an assortment of peptides. Generally, TCR affinities of peripheral T cells will be low toward self-derived peptides, as these would have been presented during thymic selection, whereas, by serendipity, binding to pathogen-derived peptides that are encountered de novo could be stronger. A crucial question in assessing immunotherapeutic strategies for cancer is whether natural TCR repertoires have the capacity for efficiently recognizing tumor-associated peptide antigens. Here, we report a comprehensive comparison of TCR affinities to a range of HLA-A2 presented antigens. TCRs that bind viral antigens fall within a strikingly higher affinity range than those that bind cancer-related antigens. This difference may be one of the key explanations for tumor immune escape and for the deficiencies of T-cell vaccines against cancer.

Figure 1. Binding parameters of virus and cancer specific TCRs to the corresponding pHLA

TCRs recognizing virus or tumor-associated antigens were isolated and prepared as described in the Materials and Methods. Binding parameters were assessed by Surface Plasmon Resonance (SPR) using a BIAcore3000. Data shown are from one experiment. The calculated values for (A) affinity (K_D) and (B) half-life (t_1/2) shown are from one independent measurement. The horizontal bar denotes the mean. For graphing purposes, TCRs with t_1/2 values, of < 0.5s were assigned a value of 0.5s. The difference between the two population means is statistical significance at the 95% confidence interval determined using an unpaired t test (p = < 0.0001 for K_D and p = 0.0028 for t_1/2). Equal variance, determined using an F test, was first achieved by taking the log of each data point. (C) The relationship between, K_D and t_1/2 is also shown. The different windows for TCR recognition of viral and tumor antigen-specific TCRs are defined by the shaded areas.