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_H17 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_H17 cells. Of clinical importance, CD26^high and T_H17 cells engineered with a chimeric antigen receptor (CAR) regressed large human tumors to a greater extent than enriched T_H1 or T_H2 cells. Only human CD26^high T cells mediated curative responses, even when redirected with a suboptimal CAR and without aid by CD8⁺ CAR T 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.