Tumor-released autophagosomes induces CD4+ T cell-mediated immunosuppression via a TLR2-IL-6 cascade
Tumor-released autophagosomes induces CD4+ T cell-mediated immunosuppression via a TLR2-IL-6 cascade
复制标题
肿瘤释放的自噬体通过 TLR2→IL-6 级联诱导 CD4 T 细胞介导的免疫抑制。
DOI：
10.1186/s40425-019-0646-5
复制
发表时间：
2019-07-12
影响因子：
10.9
通讯作者：
Wang, Li-Xin
中科院分区：
文献类型：
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作者：
Chen, Yong-Qiang;Li, Peng-Cheng;Wang, Li-Xin
背景资料：CD 4（+）T细胞是抗肿瘤免疫的关键效应子，但肿瘤细胞如何影响CD 4（+）T细胞效应子功能尚不完全清楚。肿瘤细胞释放的自噬体（TRAPs）被认为是肿瘤进展过程中宿主抗肿瘤免疫的关键调节剂。方法：将从肿瘤细胞系和肿瘤患者胸、腹水中分离的TRAPs与CD 4（+）T细胞共孵育，研究TRAPs在CD 4（+）T细胞分化和功能中的作用和机制。在小鼠模型中测试TRAP诱导的CD+ T细胞对效应T细胞功能的抑制、对调节性B细胞的诱导以及对肿瘤发生和转移的促进。热休克蛋白90 α来自癌症患者和肿瘤细胞系的恶性渗出液的TRAPs表面的HSP 90 α通过TLR 2-MyD 88-NF-κ B刺激CD 4（+）T细胞产生IL-6。kappa B信号级联。TRAPs诱导的自分泌IL-6进一步促进CD 4（+）T细胞通过STAT 3分泌IL-10和IL-21。值得注意的是，TRAPs诱导的CD 4（+）T细胞以IL-6和IL-10依赖性方式抑制CD 4（+）和CD 8（+）效应T细胞功能，并通过IL-6、IL-10和IL-21诱导产生IL-10的调节性B细胞（Bcells），从而促进肿瘤生长和转移。一致地，通过CD 4（+）T-细胞抑制肿瘤自噬体形成或IL-6分泌显著延缓肿瘤生长。结论：TRAPs表面的HSP 90 α调控了CD 4（+）T细胞的免疫抑制功能，从而促进肿瘤的生长和转移。TRAPs或其膜结合的HSP 90 α代表了逆转癌症相关免疫抑制和改善免疫治疗的重要治疗靶点。
Background: CD4(+) T cells are critical effectors of anti-tumor immunity, but how tumor cells influence CD4(+) T cell effector function is not fully understood. Tumor cell-released autophagosomes (TRAPs) are being recognized as critical modulators of host anti-tumor immunity during tumor progression. Here, we explored the mechanistic aspects of TRAPs in the modulation of CD4(+) T cells in the tumor microenvironment.Methods: TRAPs isolated from tumor cell lines and pleural effusions or ascites of cancer patients were incubated with CD4(+) T cells to examine the function and mechanism of TRAPs in CD4(+) T cell differentiation and function. TRAPs-elicited CD+ T cells were tested for their suppression of effector T cell function, induction of regulatory B cells, and promotion of tumorigenesis and metastasis in a mouse model.Results: Heat shock protein 90 alpha (HSP90 alpha) on the surface of TRAPs from malignant effusions of cancer patients and tumor cell lines stimulated CD4(+) T cell production of IL-6 via a TLR2-MyD88-NF-kappa B signal cascade. TRAPs-induced autocrine IL-6 further promoted CD4(+) T cells secretion of IL-10 and IL-21 via STAT3. Notably, TRAPs-elicited CD4(+) T cells inhibited CD4(+) and CD8(+) effector T cell function in an IL-6- and IL-10-dependent manner and induced IL-10-producing regulatory B cells (Bregs) via IL-6, IL-10 and IL-21, thereby promoting tumor growth and metastasis. Consistently, inhibition of tumor autophagosome formation or IL-6 secretion by CD4(+) T- cells markedly retarded tumor growth. Furthermore, B cell or CD4(+) T cell depletion impeded tumor growth by increasing effector T cell function.Conclusions: HSP90 alpha on the surface of TRAPs programs the immunosuppressive functions of CD4(+) T cells to promote tumor growth and metastasis. TRAPs or their membrane-bound HSP90 alpha represent important therapeutic targets to reverse cancer-associated immunosuppression and improve immunotherapy.