Stat5-/- CD4+ T cells elicit anti-melanoma effect by CD4+ T cell remolding and Notch1 activation
Stat5-/- CD4+ T cells elicit anti-melanoma effect by CD4+ T cell remolding and Notch1 activation
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Stat5-/-CD4 T 细胞通过 CD4 T 细胞重塑和 Notch1 激活引发抗黑色素瘤作用
DOI：
10.1007/s11427-021-2078-6
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发表时间：
2022-04-29
影响因子：
9.1
通讯作者：
Fu, Xin-Yuan
中科院分区：
文献类型：
--
作者：
Jin, Ke;Li, Tong;Fu, Xin-Yuan
信号转导和转录激活因子5（Stat5）已知参与调节各种辅助性T细胞亚群的分化和效应功能。然而，Stat5如何调节肿瘤浸润CD4⁺T细胞的抗肿瘤活性在很大程度上尚不清楚。在此，我们发现CD4⁺T细胞中特异性缺失Stat5的小鼠不易发生皮下和肺转移性B16黑色素瘤，且肿瘤浸润淋巴细胞（TIL5）发生重塑。特别是，我们证实Stat5缺陷的CD4⁺初始T细胞易于极化为两种Th17细胞亚型：IFN -γ⁺和IFN -γ⁻ Th17细胞，与野生型Th17细胞相比，它们通过增强Notch1通路的激活表现出更强的抗黑色素瘤活性。因此，我们的研究揭示了Stat5在调节黑色素瘤中肿瘤特异性Th17细胞分化和功能方面的一种新功能。这项研究还为靶向Stat5和其他与Th17相关的通路以开发针对黑色素瘤患者的新型免疫疗法提供了一种新的可能性。
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 (TIL5) remolding. Especially, we confirmed that Stat5-deficient CD4(+) naive T cells were prone to polarization of two subtypes of Th17 cells: IFN-gamma(+) and IFN-gamma(-) 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.