Th9 Cells Represent a Unique Subset of CD4+ T Cells Endowed with the Ability to Eradicate Advanced Tumors

The antitumor effector T helper 1 (Th1) and Th17 cells represent two T cell paradigms: short-lived cytolytic Th1 cells and “stem cell-like” memory Th17 cells. We report that Th9 cells represent a third paradigm—they are less-exhausted, fully cytolytic, and hyperproliferative. Only tumor-specific Th9 cells completely eradicated advanced tumors, maintained a mature effector cell signature with cytolytic activity as strong as Th1 cells, and persisted as long as Th17 cells in vivo. Th9 cells displayed a unique Pu.1-Traf6-NF-κB activation-driven hyperproliferative feature, suggesting a persistence mechanism rather than an antiapoptotic strategy. Th9 antitumor efficacy depended on interleukin-9 and upregulated expression of Eomes and Traf6. Thus, tumor-specific Th9 cells are a more effective CD4+ T cell subset for adoptive cancer therapy. [Display omitted] •TRP-1-Th9 but not Th1 or Th17 cells exerted a complete antitumor response in vivo•Th9 cells are less-exhausted cytolytic effectors with upregulated Eomes expression•A hyperproliferative feature enables Th9 cells to persist long in vivo•Pu.1-Traf6-NF-κB pathway is critical for Th9 cell antitumor function in vivo Lu et al. report that adaptively transferred tumor-specific CD4+ Th9 cells eradicate large established murine tumors and protect surviving mice against tumor rechallenge. Th9 cells maintain a mature effector cell signature with cytolytic activity as strong as Th1 cells and persist as long as Th17 cells in vivo.