Neoantigens drive adoptively transferred CD8 T cells to long-lived effectors mediated by lymph node trafficking

Adoptive transfer of neoantigen-reactive T lymphocytes mediates potent responses against solid tumors in patients while often limiting toxicity to normal tissues; however, the mechanisms governing the trafficking, activation, and superior antitumor function of infused T cells remain unknown. Using a clinically relevant TCR-transgenic T cell therapy model, we examined CD8 T cell responses to melanoma expressing either wild-type or mutated antigen. Neoantigen expression conferred robust tumor regression, durable cures, and long-term protective immunity. Mechanistically, T cells reacting to neoantigen exhibited enhanced cytokine and chemokine production, heightened effector function, and sustained persistence within the blood, tumor, and lymph nodes. Notably, trafficking through secondary lymphoid organs was necessary for T cell persistence and antitumor efficacy. These findings highlight the critical role of T cell trafficking to the lymph nodes in shaping neoantigen-specific antitumor responses and offers insight for improving adoptive cellular therapies.