Publication: Stromal cell diversity associated with immune evasion in human triple‐negative breast cancer

Thomas R. Cox, Aug 2020

Stromal cell diversity associated with immune evasion in human triple‐negative breast cancer

We are excited to have been part of a recent piece of work using single cell genomics to map the different cell types present with triple negative breast cancer which has recently been published in EMBO.

The work, led by Alex Swarbrick and his team here at the Garvan uncovered four new subtypes of cells within triple negative breast cancer, which contain promising new therapeutic targets for the aggressive disease. These cells produces molecules that suppress immune cells, which may help cancer cells evade the body’s immune system, and the work could lead to a new class of therapies for triple negative breast cancer.

Breast cancer stromal cell diversity

Abstract

The tumour stroma regulates nearly all stages of carcinogenesis. Stromal heterogeneity in human triple‐negative breast cancers (TNBCs) remains poorly understood, limiting the development of stromal‐targeted therapies. Single‐cell RNA sequencing of five TNBCs revealed two cancer‐associated fibroblast (CAF) and two perivascular‐like (PVL) subpopulations. CAFs clustered into two states: the first with features of myofibroblasts and the second characterised by high expression of growth factors and immunomodulatory molecules. PVL cells clustered into two states consistent with a differentiated and immature phenotype. We showed that these stromal states have distinct morphologies, spatial relationships and functional properties in regulating the extracellular matrix. Using cell signalling predictions, we provide evidence that stromal‐immune crosstalk acts via a diverse array of immunoregulatory molecules. Importantly, the investigation of gene signatures from inflammatory‐CAFs and differentiated‐PVL cells in independent TNBC patient cohorts revealed strong associations with cytotoxic T‐cell dysfunction and exclusion, respectively. Such insights present promising candidates to further investigate for new therapeutic strategies in the treatment of TNBCs.

Links

View the article on the EMBO website here

Citation

Wu S et al. Stromal cell diversity associated with immune evasion in human triple‐negative breast cancer
EMBO (2020) | doi 10.15252/embj.2019104063

Funding

This work was supported by funding from John and Deborah McMurtrie, the National Breast Cancer Foundation (NBCF) of Australia, The Petre Foundation and The Sydney Breast Cancer Foundation. A.S. is the recipient of a Senior Research Fellowship from the National Health and Medical Research Council of Australia. S.Z.W. is supported by the Australian Government Research Training Program Scholarship. S.O.T. is supported by the NBCF (PRAC 16‐006), the IIRS 19 084 and the Sydney Breast Cancer Foundation and the Family and Friends of Michael O’Sullivan. T.R.C. is supported by an NHMRC RD Wright Biomedical Career Development Fellowship, a Susan G Komen Career Catalyst Award and a Cancer Institute NSW (CINSW) fellowship. S.J. is supported by a research fellowship from the NBCF. X.S.L. is a supported by the Breast Cancer Research Foundation (BCRF‐19‐100) and the National Institute of Health of the United States (R01CA234018).