中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Histone methyltransferase WHSC1 loss dampens MHC-I antigen presentation pathway to impair IFN-gamma stimulated antitumor immunity

文献类型：期刊论文

作者Ren, Jiale7,8; Li, Ni7,8; Pei, Siyu7,8; Lian, Yannan7,8; Li, Li1; Peng, Yuchong2; Liu, Qiuli3; Guo, Jiacheng7,8; Wang, Xuege7,8; Han, Ying7,8
刊名JOURNAL OF CLINICAL INVESTIGATION
出版日期2022-04-15
卷号132期号:8页码:16
ISSN号0021-9738
DOI10.1172/JCI153167
通讯作者Li, Ni(lini@sibs.ac.cn) ; Li, Xiong(lixiong@gdpu.edu.cn) ; Lin, Moubin(lmbin@hotmail.com) ; Qin, Jun(qinjun@sibs.ac.cn)
英文摘要IFN-gamma-stimulated MHC class I (MHC-I) antigen presentation underlies the core of antitumor immunity. However, sustained IFN-gamma signaling also enhances the programmed death ligand 1 (PD-L1) checkpoint pathway to dampen antitumor immunity. It remains unclear how these opposing effects of IFN-gamma are regulated. Here, we report that loss of the histone dimethyltransferase WHSC1 impaired the antitumor effect of IFN-gamma signaling by transcriptional downregulation of the MHC-I machinery without affecting PD-L1 expression in colorectal cancer (CRC) cells. Whscl loss promoted tumorigenesis via a non-cell-autonomous mechanism in an Apc(m)(in/+) mouse model, CRC organoids, and xenografts. Mechanistically, we found that the IFN-gamma/STAT1 signaling axis stimulated WHSC1 expression and, in turn, that WHSC1 directly interacted with NLRC5 to promote MHC-I gene expression, but not that of PD-L1. Concordantly, silencing Whscl diminished MHC-I levels, impaired antitumor immunity, and blunted the effect of immune checkpoint blockade. Patient cohort analysis revealed that WHSC1 expression positively correlated with enhanced MHC-I expression, tumor-infiltrating T cells, and favorable disease outcomes. Together, our findings establish a tumor-suppressive function of WHSC1 that relays IFN-gamma signaling to promote antigen presentation on CRC cells and provide a rationale for boosting WHSC1 activity in immunotherapy.
WOS关键词MAJOR HISTOCOMPATIBILITY COMPLEX ; SYNDROME CANDIDATE 1 ; CLINICAL-RESPONSE ; LYSINE 36 ; CANCER ; ACTIVATION ; INDUCTION ; MECHANISM ; EPIGENOME ; THERAPY
资助项目National Key Research and Development Program of China[2021YFA1300601] ; National Key Research and Development Program of China[2018YFA0902700] ; National Natural Science Foundation of China[81825018] ; National Natural Science Foundation of China[82130085] ; National Natural Science Foundation of China[81773121] ; National Natural Science Foundation of China[81802818] ; Shanghai Pilot Program for Basic Research - Chinese Academy of Sciences, Shanghai Branch[JCYJ-SHFY-2022-007] ; Chinese Academy of Sciences[QYZDB-SSW-SMC052] ; Program of Shanghai Academic/Technology Research Leader[19XD1424300] ; Initiative Postdocs Supporting Program by MOHRSS ; National Postdoc Management Committee[bx201800247]
WOS研究方向Research & Experimental Medicine
语种英语
出版者AMER SOC CLINICAL INVESTIGATION INC
WOS记录号WOS:000790997000003
源URL[http://119.78.100.183/handle/2S10ELR8/299379]  
专题新药研究国家重点实验室
通讯作者Li, Ni; Li, Xiong; Lin, Moubin; Qin, Jun
作者单位1.Tongji Univ, Yangpu Hosp, Sch Med, Dept Gen Surg,Dept Gastroenterol, Shanghai, Peoples R China
2.Guangdong Pharmaceut Univ, Affiliated Hosp 1, Ctr Clin Precis Pharm, Sch Clin Pharm, Guangzhou, Peoples R China
3.Med Univ, Daping Hosp, Dept Urol, Inst Surg Res, Chongqing, Peoples R China
4.Sichuan Univ, Dept Obstet Gynecol & Pediat, Key Lab Birth Defects & Related Dis Women & Child, West China Univ Hosp 2,Minist Educ, Chengdu, Peoples R China
5.Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
7.Shanghai Jiao Tong Univ, CAS Key Lab Tissue Microenvironm & Tumor, CAS Ctr Excellence Mol Cell Sci, Sch Med SJTUSM,Shanghai Inst Nutr & Hlth, Shanghai, Peoples R China
8.Chinese Acad Sci, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Ren, Jiale,Li, Ni,Pei, Siyu,et al. Histone methyltransferase WHSC1 loss dampens MHC-I antigen presentation pathway to impair IFN-gamma stimulated antitumor immunity[J]. JOURNAL OF CLINICAL INVESTIGATION,2022,132(8):16.
APA Ren, Jiale.,Li, Ni.,Pei, Siyu.,Lian, Yannan.,Li, Li.,...&Qin, Jun.(2022).Histone methyltransferase WHSC1 loss dampens MHC-I antigen presentation pathway to impair IFN-gamma stimulated antitumor immunity.JOURNAL OF CLINICAL INVESTIGATION,132(8),16.
MLA Ren, Jiale,et al."Histone methyltransferase WHSC1 loss dampens MHC-I antigen presentation pathway to impair IFN-gamma stimulated antitumor immunity".JOURNAL OF CLINICAL INVESTIGATION 132.8(2022):16.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。