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

J Clin Invest. 2022 Apr 15;132(8):e153167. 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.

Keywords: Antigen presentation; Colorectal cancer; Epigenetics; Oncology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation
  • B7-H1 Antigen* / metabolism
  • Histone-Lysine N-Methyltransferase* / metabolism
  • Histones
  • Humans
  • Interferon-gamma
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Neoplasms*
  • Repressor Proteins*

Substances

  • B7-H1 Antigen
  • Histones
  • Intracellular Signaling Peptides and Proteins
  • NLRC5 protein, human
  • NLRC5 protein, mouse
  • Repressor Proteins
  • Interferon-gamma
  • Histone-Lysine N-Methyltransferase
  • NSD2 protein, human
  • WHSC1 protein, mouse