Human CD26high T cells elicit tumor immunity against multiple malignancies via enhanced migration and persistence

CD8 + T lymphocytes mediate potent immune responses against tumor, but the role of human CD4 + T cell subsets in cancer immunotherapy remains ill-defined. Herein, we exhibit that CD26 identifies three T helper subsets with distinct immunological properties in both healthy individuals and cancer patients. Although CD26 neg T cells possess a regulatory phenotype, CD26 int T cells are mainly naive and CD26 high T cells appear terminally differentiated and exhausted. Paradoxically, CD26 high T cells persist in and regress multiple solid tumors following adoptive cell transfer. Further analysis revealed that CD26 high cells have a rich chemokine receptor profile (including CCR2 and CCR5), profound cytotoxicity (Granzyme B and CD107A), resistance to apoptosis (c-KIT and Bcl2), and enhanced stemness (β-catenin and Lef1). These properties license CD26 high T cells with a natural capacity to traffic to, regress and survive in solid tumors. Collectively, these findings identify CD4 + T cell subsets with properties critical for improving cancer immunotherapy. The role of human CD4 + T cell subsets in cancer immunotherapy is still unclear. Here, the authors show that CD26 identifies three CD4 + T cell subsets with distinct immunological properties in both healthy individuals and cancer patients.