Hybrid Th1/17 cells possess unique immuno-metabolic phenotype and surpiror anti-tumor activity

Abstract

Immunotherapy of cancer is a promising approach for successful eradication of large and established tumor. Accumulating evidence indicates that CD4⁺ T helper (Th) cells including Th1 and Th17 subsets are also effective in tumor immunotherapy. While the anti-tumor potential of Th17 cells primarily depends upon IFN-γ secretion and persistence, a long-term tumor control has still remained elusive. In current study, we established an optimal protocol to program CD4 T cells ex vivo into a combinational phenotype of Th1 and Th17 subset (named hybrid Th1/17 cells), which express high levels of IFN-γ, CD107a, T-bet, Granzyme B, IL23R, IL22, Bcl6, and Tcf7. A detailed microaray analysis followed by Ingenutity Pathway Analysis for hybrid Th1/17 cells further established its unique molecular signature. Importantly, a comprehensive analysis for about 400 metabolites also established that hybrid Th1/17 cells have unique metaboliomic signature. Furthermore, using two types of TCR transgenic models and established B16 tumor model either administrated subcutaneously or intravenously, we demonstrated that the hybrid Th1/17 cells exhibit a superior activity in controlling tumor as compared to Th1 or Th17 alone. We observed that the unique immuno-metabolic phenotype rendered to hybrid Th1/17 cells corrected with their increased ability to survive, overcome tumor mediated immunosuppression, resulting the superior effectiveness to control tumor in long-term.