Nelson and Knochelmann et al. report that CD26high CD4+ T cells represent a distinct population of CD4+ helper T cells with potent antitumor properties. CD26high CD4+ T cells differ from TH1, TH2, and TH17 cells based on surface markers, increased cytokine production (IL-17, IFNγ, IL-22, and IL-2), epigenetic landscape, and gene expression patterns. CD26high CD4+ T cells expressing first generation mesothelin-specific CAR increased CD4+ and CD8+ CAR T cell persistence in vivo, eradicated large established mesothelioma tumors, and increased survival independent of IL-17 and CD26 expression and of CD8+ CAR T cells.
Contributed by Shishir Pant
ABSTRACT: How 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.