# Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes

Source: https://onco.cc/key-papers/paper-lehmann-tnbc-subtype-multiomics-nat-commun-2021/  
OnCo record `paper-lehmann-tnbc-subtype-multiomics-nat-commun-2021` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Nature Communications
- Year: 2021
- DOI: 10.1038/s41467-021-26502-6
- Authors: Lehmann BD, Colaprico A, Silva TC, et al.
- 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.
- What it means: 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.

## Sources

- Lehmann et al., Nat Commun 2021: multi-omics vulnerabilities of TNBC subtypes: https://doi.org/10.1038/s41467-021-26502-6
- PubMed: https://pubmed.ncbi.nlm.nih.gov/34725325/

## Connected records

- cancers: [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- targets: [EZH2](https://onco.cc/targets/ezh2/), [PD-L1](https://onco.cc/targets/pdl1/)
- institutions: [Vanderbilt-Ingram Cancer Center](https://onco.cc/institutions/vanderbilt-ingram/)
- pathways: [Antigen presentation & immune editing](https://onco.cc/pathways/antigen-presentation-immunoediting/), [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [Epithelial-mesenchymal transition & drug efflux](https://onco.cc/pathways/emt/)
- journals: [Nature Communications](https://onco.cc/journals/nature-communications/)

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