SARS-CoV-2-specific T cells cross-react with tumor-associated antigens via molecular mimicry

We have recently described SARS-COV-2 antigens showing sequence and conformational homology to tumor associated antigens (TAAs). Moreover, cross-reactive T cells have been identified in individuals either infected by the SARS-CoV-2 virus or vaccinated with the BNT162b2 preventive vaccine. In the present study, we analyzed the specific cross-binding TCRs by single cell RNA TCR sequencing.

The paired SARS-CoV-2 epitope LLLDDFVEI (VIR) and the PRDX5 tumor associated antigen LLLDDLLVS (TAA) were selected to elicit cross-reacting T cells ex vivo. PBMCs from 5 healthy individuals were cultured for 10 days with 10 ug every 3 days of one of the two peptides and cells were selected for single cell RNA TCR sequencing. Results in CD8⁺ T Effector cells (T_TE) showed the amplification or the de novo identification of a handful number of TRAV/TRBV genes and of CDR3αβ motifs upon treatment ex vivo with both epitopes, which are specific for each subject in the analysis. The very same clonotypes were identified also in the CD8⁺ T proliferating subset, confirming that both epitopes induced a highly activated and plastic state. Conformational prediction analyses of pMHC-TCR complexes showed perfect structural overlap, suggesting the functional cross-reaction of CD8 + T cells with both the viral and the tumor antigens.

Our results describe for the first time the TCR CDR3αβ motifs amplified or de novo expanded by induction with a viral antigen showing a molecular mimicry with a tumor antigen. They are strictly individual and do not match with any motif in the publicly available TCR repository. However, considering the significant degeneracy in the TCR binding to the same epitope, the finding of identical TCR CDR3αβ motifs elicited by two homologous epitopes is of the highest functional relevance. Such results provide a clear experimental validation proof that microbial epitopes mimicking TAAs can be used to develop off-the-shelf preventive/therapeutic vaccine formulations. Indeed, such non-self antigens are much stronger immunogens and may elicit a potent cross-reacting anti-cancer T cell response.