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.

自然产生的人类 CD4 ⁺ T 辅助子亚群如何影响癌症免疫治疗尚不清楚。我们报道人类 CD4 ⁺ CD26^高T 细胞可引发针对实体瘤的强效免疫。由于 CD26^高T 细胞因其 IL-17 产生和高 CD26 表达而经常被归类为 T _H 17 细胞，因此我们假设这些群体具有相似的分子特性。在这里，我们揭示了 CD26^高T 细胞在表观遗传和转录上与 T _H 17 细胞不同。具有临床重要性的是，用嵌合抗原受体（CAR）改造的 CD26 ^high和 T _H 17 细胞比富集的 T _H 1 或 T _H 2 细胞更大程度地消退了大型人类肿瘤。只有人类 CD26^高T 细胞介导治疗反应，即使在使用次优 CAR 重定向且没有 CD8 ⁺ CAR T 细胞帮助的情况下也是如此。 CD26^高T 细胞共同分泌效应细胞因子，产生细胞毒性分子，并长期持续存在。总的来说，我们的工作强调了 CD4 ⁺ T 细胞群在提高实体瘤治疗耐久性方面的前景。