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Mesenchymal triple-negative tumours hide from the immune system by switching off the machinery that displays tumour proteins to T cells; a drug class that blocks the PRC2 epigenetic complex switched it back on in mice and made chemotherapy work better.
Mutation, copy number, transcriptomic, epigenetic, proteomic and phospho-proteomic patterns were analysed across the TNBC subtypes (BL1, BL2, M, LAR). Mesenchymal tumours displayed high mutation loads, genomic instability, absence of immune cells, low PD-L1 expression, decreased global DNA methylation and transcriptional repression of antigen presentation genes. MHC class I was shown to be suppressed by H3K27me3 laid down by the polycomb repressor complex 2 (PRC2); pharmacological inhibition of the PRC2 subunits EZH2 or EED restored MHC-I expression and enhanced chemotherapy efficacy in murine tumour models.
It gives the PD-L1-negative mesenchymal subtype, the group immunotherapy leaves behind, a mechanistic route back to immune visibility, and explains why immune infiltration and subtype are coupled.
Shares Antigen presentation & immune editing, PD-L1, Triple-negative breast cancer (TNBC).
Shares EZH2, Epigenetic reprogramming, Epithelial-mesenchymal transition & drug efflux.
Shares Nature Communications, Triple-negative breast cancer (TNBC).
Shares Vanderbilt-Ingram Cancer Center, Epithelial-mesenchymal transition & drug efflux, Triple-negative breast cancer (TNBC).
Shares Epithelial-mesenchymal transition & drug efflux, Triple-negative breast cancer (TNBC).
Shares Vanderbilt-Ingram Cancer Center, Triple-negative breast cancer (TNBC).
Shares Epithelial-mesenchymal transition & drug efflux, Triple-negative breast cancer (TNBC).
Shares Epithelial-mesenchymal transition & drug efflux, Triple-negative breast cancer (TNBC).