Epitope spreading is a process whereby sub-dominant or cryptic epitopes distinct from and non-cross-reactive with the inducing, dominant epitope become targets of the evolving immune response. Epitope spreading exacerbates the pathology of autoimmune diseases in the central nervous system, however it has been reported to lead to a beneficial magnification of the anti-cancer immune response during cancer immunotherapy, where breaking of self-tolerance is desirable. Furthermore, epitope spreading has been correlated to improved patient outcomes after immunotherapy in the clinic. In particular, diversified epitope specificity is desired in order to prevent relapse after anti-cancer therapy.
To date the mechanisms underlying epitope spreading remain poorly understood. However it has been demonstrated that many immunotherapies initiate a broadened response to tumour epitopes. We have studied epitope spreading using a model of adoptive cell therapy where tumours are engineered to express ovalbumin and can be targeted by the transfer of activated OVA-specific (OT-I) T cells. Using this system we have identified endogenous T cell responses initiated against previously unrecognized epitopes indicating that epitope spreading is indeed occurring. Interestingly we have found that lymphodepletion by total body irradiation promotes the occurrence of epitope spreading.
The correlation between patient outcome and epitope spreading suggests that such immune diversification is important for effective cancer immunotherapy. Using our model we aim to better understand the kinetics and mechanisms underlying epitope spreading. In the future we plan to investigate the synergy between current immunotherapies and novel approaches which focus on increasing epitope spreading and broadening the anti-cancer immune response.