Homeoprotein SIX1 compromises antitumor immunity through TGF-β-mediated regulation of collagens  

作　　者：Wancheng Liu Meiling Gao Lili Li Yu Chen Huimin Fan Qiaomei Cai Yueyue Shi Chaohu Pan Junxiao Liu Lucy S.Cheng Heng Yang Genhong Cheng 

机构地区：[1]Institute of Systems Medicine,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing,100005,China [2]Suzhou Institute of Systems Medicine,Suzhou,215123,China [3]Department of Dermatology,University of Pittsburgh Medical Center,3708 Fifth Avenue,Suite 500.68,Pittsburgh,PA,15213,USA [4]Department of Microbiology,Immunology&Molecular Genetics,University of California,Los Angeles,CA,USA

出　　处：《Cellular & Molecular Immunology》2021年第12期2660-2672,共13页中国免疫学杂志（英文版）

基　　金：This project was financially supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-1-I2M-047,2016-I2M-1-005 and 2019-I2M-1-003);National Science funds of China(82073181,81802870,82102371 and 2017YFA0506200);Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(2020-PT310-006,2019XK310002 and 2018TX31001);HY is supported by science funds from Jiangsu Province(BK20211554,BK20170407);the Innovative and Entrepreneurial Team grant(2018-2021)from Jiangsu Province;LL is supported by the Chinese Postdoctoral Science Foundation(2019M650564);Innovative and Entrepreneurial Doctor grant(2020-2022)from Jiangsu Province.

摘　　要：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.

关 键 词：Homeoprotein SIX1 anti-tumor immunity collagens. 

分 类 号：R730.51[医药卫生—肿瘤]