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Histone methyltransferase WHSC1 loss dampens MHC-I antigen presentation pathway to impair IFN-γ-stimulated antitumor immunity

J Clin Invest. 2022-04; 
Jiale Ren, Ni Li, Siyu Pei, Yannan Lian, Li Li, Yuchong Peng, Qiuli Liu, Jiacheng Guo, Xuege Wang, Ying Han, Guoying Zhang, Hanling Wang, Yaqi Li, Jun Jiang, Qintong Li, Minjia Tan, Junjie Peng, Guohong Hu, Yichuan Xiao, Xiong Li, Moubin Lin, Jun Qin
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Recombinant Proteins … Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in … For IFN-γ treatment, 25 μg/kg IFN-γ (GenScript, Z02915) was intravenously administered … Get A Quote

摘要

IFN-γ-stimulated MHC class I (MHC-I) antigen presentation underlies the core of antitumor immunity. However, sustained IFN-γ 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-γ are regulated. Here, we report that loss of the histone dimethyltransferase WHSC1 impaired the antitumor effect of IFN-γ signaling by transcriptional downregulation of the MHC-I machinery without affecting PD-L1 expression in colorectal cancer (CRC) cells. Whsc1 loss promoted tumorigenesis via a non-cell-autonomous mechanism in an Apcmin/+ mouse model, CRC organoids, and xenografts. Mechanistically, we found that the IFN-... More

关键词

Antigen presentation, Colorectal cancer, Epigenetics, Oncology