The mechanism by which one non-self antigen augments T cell immune responses to another remains unclear. We found that these expanded immune responses could derive from chimeric non-self peptides. These peptides, which we termed complete T cell antigens (CTAs), must be expressed intracellularly as single-chain chimeras containing both MHC class I- and II-restricted epitopes. CTAs, even unrelated to tumor antigens, when administered as live cell adjuvants or in cDNA-transfected muscle, increased T cell reactivity against tumor neoantigens. Mechanistically, CTA treatment altered dendritic cell phenotype in a CD4+ T cell-dependent manner, suppressing CD8+ T cell exhaustion and generating self-renewing CD8+ T cells in tumors. Cancers predicted to have long non-self peptides resulting from frameshift mutations, which frequently contain CTAs, were associated with a better prognosis or benefit from PD-1 blockade therapy in mouse models and cancer patients. These findings indicate that a subset of cancer cells expressing CTAs is sufficient to evoke overall antitumor immunity by broadening T cell responses to other neoantigens.
© 2025 Zhang et al.