Editors' ChoiceImmunology

A new function for polycomb in immune evasion

See allHide authors and affiliations

Science Translational Medicine  16 Oct 2019:
Vol. 11, Issue 514, eaaz3718
DOI: 10.1126/scitranslmed.aaz3718

Abstract

Polycomb repressive complex 2 silences MHC class I gene expression.

Recognition and elimination of cancer cells by cytotoxic CD8+ T cells depend on presentation of antigens bound by MHC class I (MHC-I) molecules. All normal nucleated cells have cell-surface MHC-I, but expression differs by up to 100-fold across cell types, with particularly low amounts in neural tissues like brain and retina. This indicates that MHC-I expression is partially determined by tissue-specific regulatory programs, which are incompletely understood. Now, a new study links polycomb repressive complex 2 (PRC2)—a classical chromatin modifying complex that has already gained fame as a developmental regulator—to modulation of MHC-I expression and immune evasion by some cancer types, with interesting therapeutic implications.

Burr et al. performed a genome-wide CRISPR/Cas9 screen to identify negative regulators of MHC-I expression in erytholeukemia cells. They found that loss of several PRC2 members potently up-regulated expression of MHC-I genes. They validated this finding in several other cell types that typically express low levels of MHC-I, such as neuroblastoma and neuroendocrine small cell lung cancer cells. In conjunction with interferon-γ, pharmacological inhibition of PRC2 dramatically improved T cell responses to small cell lung cancer cells in vitro. Furthermore, in a genetically engineered model of small cell lung cancer that closely resembles its human counterpart, PRC2-mediated repression of MHC-I was so profound that cells could be transplanted across mouse strains without being rejected. Inhibition of PRC2 through deletion of its methyltransferase EZH2 fully restored appropriate rejection of the allogeneic transplant. The authors further showed that in embryonic stem cells and their neural but not mesenchymal derivatives, MHC-I genes exist in a bivalent and transcriptionally repressed state, containing both activating H3K4me3 marks and repressive H3K27me3 marks deposited by PRC2. These results indicate that neural differentiation programs may be coupled to MHC-I repression and immune evasion.

Burr and colleagues’ discoveries not only illuminate the molecular regulation of MHC-I expression but offer hope that EZH2 inhibitors—which are already in clinical trials—could help potentiate immune responses to neuroendocrine cancers with high somatic mutation burden but low MHC-I expression, like small cell lung cancer.

Highlighted Article

View Abstract

Navigate This Article