Homeoprotein SIX1 compromises antitumor immunity through TGF-β-mediated regulation of collagens.
Homeoprotein SIX1 compromises antitumor immunity through TGF-β-mediated regulation of collagens.
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同源蛋白 SIX1 通过 TGF-β 介导的胶原调节来损害抗肿瘤免疫。
DOI：
10.1038/s41423-021-00800-x
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发表时间：
2021-12
影响因子：
24.1
通讯作者：
Cheng G
中科院分区：
文献类型：
--
作者：
Liu W;Gao M;Li L;Chen Y;Fan H;Cai Q;Shi Y;Pan C;Liu J;Cheng LS;Yang H;Cheng G
肿瘤微环境（TME），包括浸润的免疫细胞，已知在肿瘤生长中起重要作用;然而，肿瘤免疫原性的机制尚未完全阐明。在此，我们发现了转录因子SIX 1在调节肿瘤免疫微环境中的一个意想不到的作用。基于对患者数据集的分析，我们发现SIX 1在人类肿瘤组织中上调，其表达水平与TME中的免疫细胞浸润和癌症患者的总生存率呈负相关。癌细胞中Six 1的缺失以免疫依赖性的方式显著降低了肿瘤生长，同时增强了TME中的抗肿瘤免疫。从机制上讲，SIX 1是通过TGF BR 2依赖性Smad 2/3激活途径表达多种胶原基因所必需得，TME中得胶原沉积阻碍了免疫细胞得浸润与激活.因此，我们的研究揭示了SIX 1在调节肿瘤免疫原性方面的关键作用，并为在癌症免疫治疗中靶向SIX 1提供了概念验证证据。
The tumor microenvironment (TME), including infiltrated immune cells, is known to play an important role in tumor growth; however, the mechanisms underlying tumor immunogenicity have not been fully elucidated. Here, we discovered an unexpected role for the transcription factor SIX1 in regulating the tumor immune microenvironment. Based on analyses of patient datasets, we found that SIX1 was upregulated in human tumor tissues and that its expression levels were negatively correlated with immune cell infiltration in the TME and the overall survival rates of cancer patients. Deletion of Six1 in cancer cells significantly reduced tumor growth in an immune-dependent manner with enhanced antitumor immunity in the TME. Mechanistically, SIX1 was required for the expression of multiple collagen genes via the TGFBR2-dependent Smad2/3 activation pathway, and collagen deposition in the TME hampered immune cell infiltration and activation. Thus, our study uncovers a crucial role for SIX1 in modulating tumor immunogenicity and provides proof-of-concept evidence for targeting SIX1 in cancer immunotherapy.
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