Targeting stromal cell Syndecan‐2 reduces breast tumour growth, metastasis and limits immune evasion

Tumour stromal cells support tumourigenesis. We report that Syndecan‐2 (SDC2) is expressed on a nonepithelial, nonhaematopoietic, nonendothelial stromal cell population within breast cancer tissue. In vitro, syndecan‐2 modulated TGFβ signalling (SMAD7, PAI‐1), migration and immunosuppression of patient‐derived tumour‐associated stromal cells (TASCs). In an orthotopic immunocompromised breast cancer model, overexpression of syndecan‐2 in TASCs significantly enhanced TGFβ signalling (SMAD7, PAI‐1), tumour growth and metastasis, whereas reducing levels of SDC2 in TASCs attenuated TGFβ signalling (SMAD7, PAI‐1, CXCR4), tumour growth and metastasis. To explore the potential for therapeutic application, a syndecan‐2‐peptide was generated that inhibited the migratory and immunosuppressive properties of TASCs in association with reduced expression of TGFβ‐regulated immunosuppressive genes, such as CXCR4 and PD‐L1. Moreover, using an orthotopic syngeneic breast cancer model, overexpression of syndecan‐2‐peptide in TASCs reduced tumour growth and immunosuppression within the TME. These data provide evidence that targeting stromal syndecan‐2 within the TME inhibits tumour growth and metastasis due to decreased TGFβ signalling and increased immune control. What's new? Tumour‐associated stromal cells within the tumour microenvironment play a significant role in promoting tumorigenesis. Current strategies to inhibit tumour‐associated stromal cell function must however reduce the potential side‐effects associated with affecting normal stromal cells. In this study, the authors report that Syndecan‐2 is expressed on a non‐epithelial, non‐haematopoietic, non‐endothelial stromal cell population within breast cancer tissue. Syndecan‐2 contributes to the oncogenic properties of tumour‐associated stromal cells by promoting TGF‐β signalling, tumour growth, metastasis, and immunosuppression. Altogether, the results highlight pro‐tumorigenic, immunosuppressive Syndecan‐2+ stromal cells within the breast tumour microenvironment as a potential therapeutic target.