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

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...

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Published in:	The EMBO journal Vol. 39; no. 19; pp. e104063 - n/a
Main Authors:	Wu, Sunny Z, Roden, Daniel L, Wang, Chenfei, Holliday, Holly, Harvey, Kate, Cazet, Aurélie S, Murphy, Kendelle J, Pereira, Brooke, Al‐Eryani, Ghamdan, Bartonicek, Nenad, Hou, Rui, Torpy, James R, Junankar, Simon, Chan, Chia‐Ling, Lam, Chuan En, Hui, Mun N, Gluch, Laurence, Beith, Jane, Parker, Andrew, Robbins, Elizabeth, Segara, Davendra, Mak, Cindy, Cooper, Caroline, Warrier, Sanjay, Forrest, Alistair, Powell, Joseph, O'Toole, Sandra, Cox, Thomas R, Timpson, Paul, Lim, Elgene, Liu, X Shirley, Swarbrick, Alexander
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01.10.2020 Springer Nature B.V John Wiley and Sons Inc
Subjects:	Breast cancer cancer‐associated fibroblasts Carcinogenesis Carcinogens Cell differentiation Crosstalk Cytotoxicity Development strategies EMBO03 EMBO19 Extracellular matrix Extracellular Matrix - immunology Extracellular Matrix - pathology Female Fibroblasts Gene expression Gene sequencing Growth factors Heterogeneity Humans Immune evasion Immune system Immunomodulation Immunomodulators Immunoregulation Inflammation Phenotypes Resource Ribonucleic acid RNA RNA-Seq Signatures single‐cell RNA sequencing Stromal Cells - immunology Stromal Cells - pathology stromal heterogeneity Subpopulations Surface markers T-Lymphocytes, Cytotoxic - immunology T-Lymphocytes, Cytotoxic - pathology Triple Negative Breast Neoplasms - immunology Triple Negative Breast Neoplasms - pathology triple‐negative breast cancer Tumor Escape Tumors tumour microenvironment tumour microenvironment cancer‐associated fibroblasts triple‐negative breast cancer stromal heterogeneity single‐cell RNA sequencing single-cell RNA sequencing cancer-associated fibroblasts triple-negative breast cancer
ISSN:	0261-4189, 1460-2075, 1460-2075
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Summary:	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. Synopsis This single‐cell gene expression resource deciphers the composition of triple‐negative breast cancer (TNBC) stroma, revealing distinct subclasses of cancer‐associated fibroblasts (CAFs) and perivascular‐like (PVL) cells. These signatures are informative on tumour aetiology and potential strategies for development of targeted therapies. Single‐cell analysis of primary TNBC highlights clusters of stromal and immune cell types. TNBC stroma is comprised of myofibroblast‐like CAFs, inflammatory‐like CAFs, differentiated PVL and immature PVL cells. Stromal subclasses differ in surface markers, spatial localisation in tissue, ECM functions, and predicted cellular crosstalk with immune cells. Inflammatory‐like CAF and differentiated PVL cells are associated with cytotoxic T‐cell dysfunction and exclusion in independent TNBC‐patient cohorts. Graphical Abstract Single‐cell profiling of primary breast cancer provides unprecedented insights into cell‐type heterogeneity within the tumor microenvironment.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 See also: F Brod & R Fässler (October 2020)
ISSN:	0261-4189 1460-2075 1460-2075
DOI:	10.15252/embj.2019104063