Single-cell analysis reveals diverse stromal subsets associated with immune evasion in triple-negative breast cancer

• DOI: 10.1101/2020.06.04.135327
• Publication Date: 2020-06-06T20:17:03Z
• Authors: Sunny Z. Wu; Daniel L. Roden; Chenfei Wang; Holly Holliday; Kate Harvey; Aurélie S. Cazet; Kendelle J. Murphy; Brooke Pereira; Ghamdan Al-Eryani; Nenad Bartonicek; Rui Hou; James R. Torpy; Simon Junankar; Chia-Ling Chan; Eric Lam; Mun N. Hui; Laurence Gluch; Jane Beith; Andrew Parker; Elizabeth Robbins; Davendra Segara; Cindy Mak; Caroline Cooper; Sanjay Warrier; Alistair Forrest; Joseph Powell; Sandra O’Toole; Thomas R. Cox; Paul Timpson; Elgene Lim; X. Shirley Liu; Alexander Swarbrick
• Keywords: Triple-negative breast cancer; Cancer-Associated Fibroblasts; Crosstalk

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