Identification of human CD4+T cell populations with distinct antitumor activity

How naturally arising human CD4 + T helper subsets impact tumor immunity is unknown. We reported that human CD4 + CD26 high T cells elicit potent immunity against solid tumor malignancies. As CD26 high T cells secrete type-17 cytokines and have been categorized as Th17 cells, we posited these helper populations would possess similar molecular properties. Herein, we reveal that CD26 high T cells are epigenetically and transcriptionally distinct from Th17 cells. Of clinical significance, CD26 high T cells engineered with a chimeric antigen receptor (CAR) ablated large human tumors to a greater extent than enriched Th17, Th1, or Th2 cells. Moreover, CD26 high T cells mediated curative responses in mice, even when redirected with a suboptimal CAR and without the aid of CD8 + CAR T cells. CD26 high T cells co-secreted effector cytokines at heightened levels and robustly persisted. Collectively, our work reveals the potential of human CD4 + T cell populations to improve durability of solid tumor therapies.