Nelson, Michelle H.Knochelmann, Hannah M.Bailey, Stefanie R.Huff, Logan W.Bowers, Jacob S.Majchrzak-Kuligowska, KingaWyatt, Megan M.Rubinstein, Mark P.Mehrotra, ShikharNishimura, Michael I.Armeson, Kent E.Giresi, Paul G.Zilliox, Michael J.Broxmeyer, Hal E.Paulos, Chrystal M.2021-05-262021-05-262020-07-01Nelson, M. H., Knochelmann, H. M., Bailey, S. R., Huff, L. W., Bowers, J. S., Majchrzak-Kuligowska, K., Wyatt, M. M., Rubinstein, M. P., Mehrotra, S., Nishimura, M. I., Armeson, K. E., Giresi, P. G., Zilliox, M. J., Broxmeyer, H. E., & Paulos, C. M. (2020). Identification of human CD4+ T cell populations with distinct antitumor activity. Science Advances, 6(27), eaba7443. https://doi.org/10.1126/sciadv.aba74432375-2548https://hdl.handle.net/1805/26025How naturally arising human CD4+ T helper subsets affect cancer immunotherapy is unclear. We reported that human CD4+CD26high T cells elicit potent immunity against solid tumors. As CD26high T cells are often categorized as TH17 cells for their IL-17 production and high CD26 expression, we posited these populations would have similar molecular properties. Here, we reveal that CD26high T cells are epigenetically and transcriptionally distinct from TH17 cells. Of clinical importance, CD26high and TH17 cells engineered with a chimeric antigen receptor (CAR) regressed large human tumors to a greater extent than enriched TH1 or TH2 cells. Only human CD26high T cells mediated curative responses, even when redirected with a suboptimal CAR and without aid by CD8+ CAR T cells. CD26high 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.en-USAttribution-NonCommercial-NoDerivatives 4.0 Internationalfibroblastsepithelialimmune cellsCD26CD4+ T helpercancer immunotherapyArticle