Objective/Rationale
Triple negative breast cancer (TNBC) represents one of the most challenging breast cancer types to treat with limited therapeutic options available currently. Recent studies of the tumour microenvironment (TME) have revealed important roles of stromal cells in regulating anti-tumour immunity. Here, we investigate how stromal cells contribute to T-cell suppression and as a potential therapeutic target to overcome this.
Design/Method
Using TNBC patient derived stromal cells and peripheral blood mononuclear cells (PBMC) from healthy donors, we performed co-culture assays and applied flow cytometry and single-cell RNA sequencing (scRNA) to assess stromal-immune interaction in vitro. A high throughput drug screen was performed to identify novel stromal-targeting drug candidates which could reverse stromal induced immunosuppression in our co-culture model.
Results
Patient derived stromal cells suppressed the proliferative capability of both CD4+ and CD8+ T-cells in vitro. scRNA of these co-culture models demonstrate that stromal co-cultured T-cells are driven into LAG3+ exhausted state enriched for canonical pathways of immunosuppressive cytokine signalling. Drug screen identified Talabostat as a novel candidate which shifts stromal cell population from predominately myofibroblasts-like cancer-associated fibroblasts (myCAF, PDGFR+ / ACTA2+) into non-myofibroblasts-like CAF cells (PDGFR+ / ACTA2-) via suppression of ACTA2 expression. Talabostat treatment in the co-culture model reversed stromal-induced suppression of CD4+ and CD8+ T-cell proliferation.
Conclusions
Talabostat reversed stromal cell mediated suppression of T-cell proliferation in vitro and is a potential candidate to elicit a more effective immune response in treatment of TNBC warranting further investigations.