Histone methyltransferase WHSC1 loss dampens MHC-I antigen presentation pathway to impair IFN-γ–stimulated antitumor immunity
Jiale Ren, … , Moubin Lin, Jun Qin
Jiale Ren, … , Moubin Lin, Jun Qin
Published March 1, 2022
Citation Information: J Clin Invest. 2022;132(8):e153167. https://doi.org/10.1172/JCI153167.
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Research Article Oncology

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

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

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Figure 7

The IFN-γ/WHSC1 axis stimulates MHC-I expression.

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The IFN-γ/WHSC1 axis stimulates MHC-I expression. (A) Heatmap showing th...
(A) Heatmap showing the mRNA levels of Whsc1 in MC38 and CT26 cells treated with the indicated cytokine (24 h), normalized to the mean level of the vehicle treatment. (B) IB analysis of CRC cells under IFN-γ treatment. (C) IB analysis of CT26 cells treated as indicated. (D) Cell-surface HLA-A/B/C expression in the indicated CRC organoid–derived tumor lysates with or without 3 consecutive days of IFN-γ treatment (25 μg/kg, n = 4). (E) Immunostaining for B2M and WHSC1 in CRC organoid–derived tumors. Scale bar: 20 μm. (F) ChIP-Seq tracks of STAT1 ChIP-Seq signals at the Whsc1 gene locus (GSE31477), and ChIP-qPCR analysis of STAT1 binding (n = 3). (G) Cell-surface SIINFEKL: H2-Kb in WT or Whsc1-KO MC38-OVA cells with or without IFN-γ treatment. The quantified MFI is shown (n = 5). (H) Viability of MC38-OVA cells after 48 hours of coculturing with OT-1 T cells (n = 3). (I) Tumor growth in C57BL/6 mice subcutaneously injected with WT or Ifngr1-KO MC38 cells with or without Whsc1 deletion (n = 6). (J) Violin plot showing the signals across peaks for MHC-I–related genes or STAT1 targets that lost chromatin accessibility following Whsc1 or Nlrc5 KO. The solid and dotted lines show the median and quartiles, respectively, with the whiskers extending to the largest and smallest values. (K) ATAC-Seq tracks at the genomic loci of MHC-I–related genes (Tap1 and H2-d) and STAT1 targets (Cd274 and Ifit2). Scale bars: 5 kb. Data are presented as the mean ± SEM. *P < 0.05 and **P < 0.01, by 2-tailed Student’s t test (D and F), 2-way ANOVA followed by multiple comparisons (G–I), and 1-way ANOVA followed by multiple comparisons (J).