Cross-competition shapes CD8+ T cell hierarchies and fate after cancer neoantigen RNA vaccination

Cancer patients typically mount T cell responses to only a small fraction of the neoantigens encoded in their individualized vaccine. Because each patient’s neoantigen set is unique, clinical studies cannot determine whether this restricted breadth reflects limitations of neoantigen prediction algorithms or intrinsic immunological constraints. Here, using a clinically relevant multi-neoantigen RNA–lipoplex vaccine in a preclinical model, we mechanistically dissected CD8+ T-cell breadth. We found that concurrently primed neoantigen-specific CD8+ T cells competed through a peptide-MHC-I-dependent cross-competition, with dominant responses suppressing both the magnitude and differentiation of subdominant responses. Dominant CD8+ T cell responses preferentially acquired a terminally differentiated effector phenotype, while sub-dominant responses adopted memory-precursor and stem-like features. Removing dominant responses enabled sub-dominant responses to expand and adopt terminally differentiated effector phenotypes. These findings provide the first mechanistic explanation for restricted CD8+ T cell breadth in multi-neoantigen vaccination and provide a framework for further optimizing cancer vaccine design.