A dominant antigen is necessary but not sufficient for effective neoantigen vaccination in murine mesothelioma

Abstract Neoantigen vaccines have emerged as a promising strategy for personalised cancer treatment, however the features of neoantigen vaccines that confer effective tumour protection remain poorly defined. Further, their application for low tumour mutation burden (TMB) cancers has been largely unexplored. We hypothesised that vaccines targeting spontaneously immunogenic neoantigens would provide superior protection to neoantigens that induce de novo T-cell responses post vaccination. We also hypothesised that increasing the breadth of neoantigen targets or including a dominant antigen would enhance vaccine efficacy. In a mouse model of the low TMB cancer mesothelioma, only vaccines that combine a dominant antigen, spontaneously recognised antigens, and neoantigens with vaccine-inducible T-cell responses conferred protection, however immunoediting of only the dominant antigen was sufficient for vaccine failure. This study highlights potential antigen dominance hierarchies that can influence vaccine efficacy and demonstrates the feasibility of neoantigen vaccines in mesothelioma, with potential implications for other low TMB tumours.