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

作者：Ren, Jiale; Li, Ni^*; Pei, Siyu; Lian, Yannan; Li, Li; Peng, Yuchong; Liu, Qiuli; Guo, Jiacheng; Wang, Xuege; Han, Ying; Zhang, Guoying; Wang, Hanling; Li, Yaqi; Jiang, Jun; Li, Qintong; Tan, Minjia; Peng, Junjie; Hu, Guohong; Xiao, Yichuan; Li, Xiong^*; Lin, Moubin^*; Qin, Jun^*

来源：Journal of Clinical Investigation, 2022, 132(8): e153167.

DOI：10.1172/JCI153167

• MAJOR HISTOCOMPATIBILITY COMPLEX
• SYNDROME CANDIDATE 1
• CLINICAL-RESPONSE
• LYSINE 36
• CANCER
• ACTIVATION
• INDUCTION
• MECHANISM
• EPIGENOME
• THERAPY

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.

• 单位
  四川大学; 复旦大学; 1; 广东药学院; 中国科学院; 上海交通大学; 同济大学; 中国医科大学