Abstract Adoptive T cell therapy (ACT) has demonstrated remarkable efficacy in treating hematological cancers. However, its efficacy against solid tumors remains limited and the emergence of cancer cells that lose expression of targeted antigens often promotes resistance to ACT. Importantly, the mechanisms underlying effective and durable ACT-mediated tumor control are incompletely understood. Here, we show that adoptive transfer of TCR-transgenic CD8 + T cells eliminates established murine melanoma tumors, with concomitant accumulation of tumor-infiltrating CD8 + T cells exhibiting both progenitor-exhausted and terminally-differentiated phenotypes. Interestingly, host CD8 + T cells contributed to ACT-mediated elimination of primary tumors and rejected ACT-resistant melanoma cells lacking the targeted antigen. Mechanistically, ACT induced TNF-α- and cross-presenting dendritic cell-dependent tumor accumulation of endogenous CD8 + T cells and effective tumor elimination. Importantly, although lymphodepleting preconditioning enhanced ACT-mediated tumor elimination, it abrogated host antitumor immunity and protection against ACT-resistant melanoma cells. Enrichment of transcriptional signatures associated with TNF-α signaling, cross-presenting dendritic cells and tumor-specific CD8 + T cells in human melanoma tumors correlated with favorable responses to ACT and increased survival. Our findings reveal that long-term efficacy of ACT is determined by the interplay between transferred and endogenous CD8 + T cells and is undermined by lymphodepleting preconditioning, which ultimately favors ACT resistance.

Long-term efficacy of adoptive cell therapy is determined by host CD8+ T cells and undermined by lymphodepleting preconditioning