{"entity":{"id":"paper-lehmann-tnbc-subtype-multiomics-nat-commun-2021","kind":"paper","name":"Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes","aka":[],"tldr":"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.","summary":"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.","asOf":"2026-09-24","links":[{"label":"Lehmann et al., Nat Commun 2021: multi-omics vulnerabilities of TNBC subtypes","url":"https://doi.org/10.1038/s41467-021-26502-6"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/34725325/"}],"tags":[],"related":[],"cancers":["tnbc"],"sections":[],"technologies":[],"targets":["ezh2","pdl1"],"drugs":[],"companies":[],"institutions":["vanderbilt-ingram"],"pathways":["antigen-presentation-immunoediting","emt","epigenetic-reprogramming"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-communications"],"dependsOn":[],"notes":[],"journal":"Nature Communications","year":2021,"doi":"10.1038/s41467-021-26502-6","pmid":"34725325","authors":"Lehmann BD, Colaprico A, Silva TC, et al.","paperType":"translational","findings":["Mesenchymal subtype: high mutation load, no immune cells, low PD-L1, repressed antigen presentation.","MHC-I is silenced by PRC2-mediated H3K27me3; EZH2 or EED inhibition restores it and improves chemotherapy in mice."],"whatItMeans":"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.","caveats":["Therapeutic evidence is in mouse models only.","Subtype calls on TCGA and METABRIC depend on purity and the classifier version."],"changedPractice":false},"route":"/key-papers/paper-lehmann-tnbc-subtype-multiomics-nat-commun-2021/","neighbours":{"cancer":[{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"target":[{"id":"ezh2","kind":"target","name":"EZH2","route":"/targets/ezh2/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"}],"institution":[{"id":"vanderbilt-ingram","kind":"institution","name":"Vanderbilt-Ingram Cancer Center","route":"/institutions/vanderbilt-ingram/"}],"pathway":[{"id":"antigen-presentation-immunoediting","kind":"pathway","name":"Antigen presentation & immune editing","route":"/pathways/antigen-presentation-immunoediting/"},{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"emt","kind":"pathway","name":"Epithelial-mesenchymal transition & drug efflux","route":"/pathways/emt/"}],"journal":[{"id":"nature-communications","kind":"journal","name":"Nature Communications","route":"/journals/nature-communications/"}]}}