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

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

doi:10.1172/jci153167

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.

Highlights

MHC class I (MHC-I) molecules, in complex with β-2-microglobulin (B2M), are loaded with endogenous peptides generated by the proteasome and imported into the ER by the heterodimeric TAP1/TAP2 transporter [1]
Reduced expression or activity of NLRC5 caused by promoter methylation, copy number loss, or somatic mutations is tightly associated with decreased MHC-I expression, impaired cytotoxic T cell activation, and unfavorable disease outcomes [11]
We further showed that Wolf-Hirschhorn syndrome candidate 1 (WHSC1) occupancies and H3K36me2 modifications on the promoter regions of NLRC5-target MHC-I genes were significantly attenuated by the deletion of Nlrc5 (Supplemental Figure 4F)

Summary

Introduction

MHC class I (MHC-I) molecules, in complex with β-2-microglobulin (B2M), are loaded with endogenous peptides generated by the proteasome and imported into the ER by the heterodimeric TAP1/TAP2 transporter [1]. A decrease in or absence of MHC-I expression results in tumor immune escape and failure of immunotherapy largely due to a lack of tumor antigen presentation to recruit and activate CD8+ cytotoxic T lymphocytes [2]. MHC-I downregulation occurs through genomic mutations and via nongenomic mechanisms that exploit the epigenetic and transcriptional silencing of the MHC locus and/or the antigen-processing machinery [7]. NLRC5, known as MHC class I transactivator (CITA), is an IFN-γ–inducible nuclear protein lacking a DNA-binding domain and is tethered to the enhanceosome to occupy the MHC-I gene locus containing an SXY module [8]. Reduced expression or activity of NLRC5 caused by promoter methylation, copy number loss, or somatic mutations is tightly associated with decreased MHC-I expression, impaired cytotoxic T cell activation, and unfavorable disease outcomes [11]

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