Hirsutella Sinensis Fungus Regulates CD8(+) T Cell Exhaustion Through Involvement of T-Bet/Eomes in the Tumor Microenvironment.
Hirsutella Sinensis Fungus Regulates CD8(+) T Cell Exhaustion Through Involvement of T-Bet/Eomes in the Tumor Microenvironment.
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中华被毛真菌通过 T-bet/Eomes 参与肿瘤微环境调节 CD8 T 细胞耗竭
DOI：
10.3389/fphar.2020.612620
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发表时间：
2020
影响因子：
5.6
通讯作者：
Fu H
中科院分区：
文献类型：
--
作者：
Jin L;Jin L;Wu R;Liu X;Zhu X;Shou Q;Fu H
背景：靶向耗竭的T（Tex）细胞是一种有前途的抗肿瘤治疗策略。之前，我们证明了中国被毛孢真菌（HSF）可以显著增加肿瘤微环境中的T细胞浸润和效应T细胞比例，激活全身免疫反应。然而，我们不知道HSF如何调节肿瘤微环境中的Tex细胞。在此，我们探讨了HSF抑制Tex细胞和乳腺癌肿瘤生长和转移的机制。 方法：采用活体成像技术研究HSF对多种肿瘤小鼠模型的影响。H&E染色检测肺转移，流式细胞术检测肿瘤微环境中T细胞亚群。检测CD 8 + T细胞的体外增殖、功能、凋亡及T-bet、PD-1 mRNA的表达。 结果如下：HSF抑制小鼠肿瘤生长和肺转移，并且在肿瘤浸润的CD 8 + T细胞中具有显著较高的CD 44 LowCD 62 LHi和CD 44 HiCD 62 LLow群体。然而，HSF显著降低抑制性受体如PD-1、TIGIT、CTLA-4和调节性T细胞的水平。体外实验表明，HSF可抑制CD 8 + T细胞凋亡率，促进CD 8 + T细胞增殖，促进IFN-γ和颗粒酶B的分泌。此外，体内和体外HSF处理均显著增加Eomes表达，同时降低T-bet表达。 结论：HSF主要通过免疫系统发挥抗肿瘤作用，通过促进效应/记忆T细胞和减少肿瘤微环境中的Tex细胞产生。其具体机制分别涉及抑制T-bet和促进Eomes减少免疫抑制剂受体的表达和增强T细胞功能。
Background: Targeting exhausted T (Tex) cells is a promising strategy for anti-tumour treatment. Previously, we demonstrated that Hirsutella sinensis fungus (HSF) could significantly increase T cell infiltration and the effector T cell ratio in the tumor microenvironment, activating systemic immune responses. However, we do not know how HSF regulates Tex cells in the tumor microenvironment. Here, we explored the mechanism underlying HSF inhibition of Tex cells and tumor growth and metastasis in breast cancer. Methods: We examined the effects of HSF on various tumor mouse models using in vivo imaging technology. Lung metastasis was detected by H&E staining and the T cell subsets in the tumor microenvironment were assayed with flow cytometry. The in vitro proliferation, function and apoptosis of CD8+ T cells were measured, as well as the T-bet and PD-1 mRNA expressions. Results: HSF inhibited tumor growth and lung metastasis in the mice, and had significantly higher CD44LowCD62LHi and CD44HiCD62LLowpopulations in the tumour-infiltrating CD8+ T cells. However, HSF significantly reduced levels of inhibitory receptors, such as PD-1, TIGIT, CTLA-4, and regulatory T cells. In vitro, HSF inhibited the CD8+ T cell apoptosis rate, and promoted CD8+ T cell proliferation and secretion of interferon (IFN)-γ and granzyme B. Furthermore, HSF treatment both in vivo and in vitro significantly increased Eomes expression, while decreasing T-bet expression. Conclusion: HSF exerted anti-tumour effects mainly through the immune system, by promoting effector/memory T cells and reducing Tex cell production in the tumor microenvironment. The specific mechanisms involved inhibiting T-bet and promoting Eomes to decrease the expression of immune inhibitor receptors and enhance the T cell function, respectively.
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