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

This study is led by Prof. Xin-Yuan Fu and Dr. Ke Jin from Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University. Tumor-infiltrating lymphocytes (TILs) play a key role in the antitumor immune response and various types of immunotherapies. Recently, accumulating studies have shown that CD4⁺ T cells and CD8⁺ T cells are equally important for an efficient antitumor immune response, and in specific tumor settings, CD4⁺ T cell-mediated tumor killing effects can even outcompete that of CD8⁺ T cells. Immunosuppressive signals in the tumor microenvironment (TME) can inhibit the infiltration and activity of TILs, while remodeling of CD4⁺ T cell subsets may alter the cellular components of TILs, thereby enhancing their antitumor immune activity. However, the underlying mechanisms by which CD4⁺ T cells are involved in reshaping the TME need to be further elucidated.

Stat5, one of the transcriptional factors downstream of common gamma chain (γc) and janus kinase (JAK), plays a critical role in controlling T cell homeostasis and determining the fate of T cell subsets. However, Stat5 seems to play a more complex role in regulating CD4⁺ T cell-mediated immune response in different immunologic contexts, raising a concern about how Stat5 acts to boost or repress antitumor immunity exerted by CD4⁺ T cells in solid tumors.

In the current study, the authors found that subcutaneously inoculated B16 melanoma cells were significantly repressed in Stat5^fl/flCd4-Cre mice compared to their wild type (WT) littermates. By performing RNA sequencing to analyze the transcriptomic differences of CD4⁺ TILs in the melanoma isolated from Stat5^fl/flCd4-Cre and WT tumor-bearing mice, they found that Th17-related molecules were significantly enriched in the Stat5^fl/flCd4-Cre CD4⁺ TILs compared to WT CD4⁺ TILs. Especially, they found that deficiency of Stat5 in CD4⁺ T cells resulted in increased conventional Th17 cells (IL-17A⁺ IFN-γ^-) and, the unconventional Th17 cells (IL-17A⁺ IFN-γ⁺) which resembled the phenotype of Th1 cells in TILs and were defined as Th1-like Th17 cells. They also confirmed that Stat5-deficient CD4⁺ naïve T cells were prone to polarization of two subtypes of Th17 cells mentioned above, which exhibited increased anti-melanoma activity through enhanced activation of Notch1 pathway compared to WT Th17 cells.

In conclusion, the current study reveals that Stat5 probably plays a suppressive role in CD4⁺ T cell-mediated anti-melanoma responses and offers a possibility for targeting Stat5 to develop new T-cell-based antitumor immunotherapy.

See the article:

Stat5^-/- CD4⁺ T cells elicit anti-melanoma effect by CD4⁺ T cell remolding and Notch1 activation

https://doi.org/10.1007/s11427-021-2078-6

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