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

Histone methyltransferase WHSC1 loss dampens MHC-I antigen presentation pathway to impair IFN-gamma stimulated antitumor immunity
Author Ren, JL; Li, N; Pei, SY; Lian, YN; Li, L; Peng, YC; Liu, QL; Guo, JC; Wang, XG; Han, Y; Zhang, GY; Wang, HL; Li, YQ; Jiang, J; Li, QT; Tan, MJ; Peng, JJ; Hu, GH; Xiao, YC; Li, X; Lin, MB; Qin, J
Journal JOURNAL OF CLINICAL INVESTIGATION
Pub Year 2022
Type Article
Abstract 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.
Issue 132
Volume 132