Stat5 CD4 T cells elicit anti-melanoma effect by CD4 T cell remolding and Notch1 activation.

Signal transducers and activators of transcription 5 (Stat5) is known to engage in regulating the differentiation and effector function of various subsets of T helper cells. However, how Stat5 regulates the antitumor activity of tumor-infiltrating CD4 T cells is largely unknown. Here, we showed that mice with specific deletion of Stat5 in CD4 T cells were less susceptible to developing subcutaneous and lung metastatic B16 melanoma with CD4 tumor-infiltrating lymphocytes (TILs) remolding. Especially, we confirmed that Stat5-deficient CD4 naïve T cells were prone to polarization of two subtypes of Th17 cells: IFN-γ and IFN-γ Th17 cells, which exhibited increased anti-melanoma activity through enhanced activation of Notch1 pathway compared with wild type Th17 cells. Our study therefore revealed a novel function of Stat5 in regulating tumor-specific Th17 cell differentiation and function in melanoma. This study also provided a new possibility for targeting Stat5 and other Th17-associated pathways to develop novel immunotherapies for melanoma patients.