Lymphodepleting preconditioning impairs host antitumor immunity induced by adoptive T cell therapy in mouse models.

Abstract

Adoptive T cell therapy (ACT) is effective against hematologic cancers, but the mechanisms underlying durable responses in solid tumors remain unclear. We show that adoptively transferred CD8T cells that eradicate established murine tumors promote expansion of host CD8T cells exhibiting tumor-reactive and tissue-resident phenotypes that contribute to tumor elimination. Mechanistically, tumor necrosis factor (TNF) from transferred cells induces dendritic cell (DC)-dependent expansion of host CD8T cells, conferring protection against ACT-resistant tumor cells lacking the targeted antigen. Lymphodepleting preconditioning promotes expansion of transferred cells and primary tumor eradication but impairs host antitumor immunity and abrogates protection against ACT-resistant tumors. In human tumors, increased TNF/DC/CD8T cell profiles correlate with favorable ACT responses and improved survival. These findings reveal a TNF-dependent interplay between transferred and host CD8T cells underlying durable antitumor immunity that is impaired by lymphodepleting preconditioning in mouse models, suggesting an underappreciated mechanism of ACT resistance.