Heat shock proteins may be a missing link between febrile infection and cancer tumor rejection via autoantigen molecular mimicry

Numerous epidemiological studies suggest febrile infections could confer long-term immunity to certain types of cancers, though the precise mechanisms for this phenomenon remain unclear. Systemic heat-shock responses to fever may be key to understanding the overlapping outcomes of immune responses to infection and cancer. To investigate this hypothesis, we performed epitope discovery between heat-shock proteins (HSP) and cancer-associated antigens (CAA) and annotated the results with experimentally validated epitopes in the Immune Epitope Database (IEDB) (Vita et al., 2019). Further, epitopes were matched with their homologs in human pathogens. Results identified 94 epitopes shared between HSPs and CAAs, with experimental evidence of presentation at MHC molecules and with high homology to several epitopes of human pathogens. The identified epitopes can be used as candidates for designing cancer vaccines. They may also be used to identify autoreactive antibodies or TCR specificities that, as antibody drugs and cell therapies, would reproduce the effect of febrile infection in conferring cancer immunity. Our results support the hypothesis that the loss of self-tolerance to HSPs during febrile infection confers tumor immunity through molecular mimicry.