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

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.

Fibroblasts direct differentiation of human breast epithelial progenitors

“…Whether the breast cancer repertoire of CAFs is a caricature and maybe even a reminiscence of the normal stromal cell heterogeneity remains an open question. Interestingly, however, recent single-cell RNA sequencing of breast carcinomas has resolved stromal cell diversity to include both myofibroblastic and inflammatory CAFs and not least perivascular cells [60,61]. While this concurs with our early studies, which suggested diverse cellular origins of CAFs, including resident fibroblasts and perivascular cells [62,63], our present findings suggest that lineage heterogeneity within the resident fibroblast compartment adds to the complexity.…”

Tumour Stroma Ratio Assessment Using Digital Image Analysis Predicts Survival in Triple Negative and Luminal Breast Cancer

“…High stroma has been associated with poor prognosis in several studies [ 10 , 11 , 12 ] with favourable outcome in one study [ 13 ]. Single cell transcriptomic studies have identified the diverse phenotype of cells present in the TME, which include immune cells, cancer associated fibroblasts (CAFs), endothelial cells and pericytes [ 6 , 14 ]. There is increasing evidence to suggest that CAFs may provide a specialised niche for cancer stem cells and influence responsiveness to chemotherapy in TNBC [ 5 , 15 , 16 ] and endocrine therapy in ER+ disease [ 17 , 18 ], supported by more recent single cell sequencing studies identifying specific subtypes of CAFs in mouse and human breast tumours [ 14 , 19 ].…”

“…Single cell transcriptomic studies have identified the diverse phenotype of cells present in the TME, which include immune cells, cancer associated fibroblasts (CAFs), endothelial cells and pericytes [ 6 , 14 ]. There is increasing evidence to suggest that CAFs may provide a specialised niche for cancer stem cells and influence responsiveness to chemotherapy in TNBC [ 5 , 15 , 16 ] and endocrine therapy in ER+ disease [ 17 , 18 ], supported by more recent single cell sequencing studies identifying specific subtypes of CAFs in mouse and human breast tumours [ 14 , 19 ]. Therefore, further data to support the rationale for including TSR as a prognostic variable in breast cancer, with clinical significance, especially for TNBC which has no other existing biomarkers, would be of value in patient risk stratification.…”

3D Bioprinted cancer models: Revolutionizing personalized cancer therapy

“…For instance, a brain tumor construct should be based on patient-derived tumor cells of interest mixed with surrounding healthy brain cells including neurons, glial cells, astrocytes, and microvascular endothelial cells [ 80 , 81 ]. However, a breast cancer construct should be designed in such a way that patient-derived breast cancer cells are surrounded by mammary epithelial cells, adipocytes, fibroblasts, and endothelial cells [ 82 , 83 ]. This approach facilitates recapitulation of the tumor type as well as the target tissue.…”