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

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Abstract

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-γ/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 Whsc1 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-γ signaling to promote antigen presentation on CRC cells and provide a rationale for boosting WHSC1 activity in immunotherapy.

Authors

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