Pathogen-Boosted Adoptive Cell Transfer Therapy Induces Endogenous Antitumor Immunity through Antigen Spreading

Loss of target antigens in tumor cells has become one of the major hurdles limiting the efficacy of adoptive cell therapy (ACT)-based immunotherapies. The optimal approach to overcome this challenge includes broadening the immune response from the initially targeted tumor-associated antigen (TAA) to other TAAs expressed in the tumor. To induce a more broadly targeted antitumor response, we utilized our previously developed Re-energized ACT (ReACT), which capitalizes onthe synergistic effect ofpathogen-based immunotherapy and ACT. In this study, we showed that ReACT induced a sufficient endogenousCD8(+) T-cell response beyond the initial target to prevent the outgrowth of antigen loss variants in a B16-F10 melanoma model. Sequentially, selective depletion experiments revealed that Batf3-driven cDC1s were essential for the activation of endogenous tumor-specific CD8(+) T cells. In ReACT-treated mice that eradicated tumors, we observed that endogenousCD8(+) Tcells differentiated into memory cells and facilitated the rejection of local and distal tumor rechallenge. By targeting one TAA with ReACT, we provided broader TAA coverage to counter antigen escape and generate a durable memory response against local relapse and metastasis.