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

How naturally arising human CD4(+) T helper subsets affect cancer immunotherapy is unclear. We reported that human CD4(+)CD26(high) T cells elicit potent immunity against solid tumors. As CD26(high) T cells are often categorized as T(H)17 cells for their IL-17 production and high CD26 expression, we posited these populations would have similar molecular properties. Here, we reveal that CD26(high) T cells are epigenetically and transcriptionally distinct from T(H)17 cells. Of clinical importance, CD26(high) and T(H)17 cells engineered with a chimeric antigen receptor (CAR) regressed large human tumors to a greater extent than enriched T(H)1 or T(H)2 cells. Only human CD26(high) T cells mediated curative responses, even when redirected with a suboptimal CAR and without aid by CD8(+) CART cells. CD26(high) T cells cosecreted effector cytokines, produced cytotoxic molecules, and persisted long term. Collectively, our work underscores the promise of CD4(+) T cell populations to improve durability of solid tumor therapies.