11P - Targeting stromal cells to reverse immune suppression in triple-negative breast cancer

Background

Although there have been some positive results, the success of immune checkpoint inhibition in triple-negative breast cancer (TNBC) to date remains rather limited. A better understanding of mechanisms of immune evasion other than via PD1/PD-L1 axes and how to overcome these is therefore much needed to improve the efficacy of immunotherapy in this poor prognosis disease. Recent studies of the tumour microenvironment (TME) have elucidated the heterogeneity of stromal cells and suggested that stromal subsets play an important role in regulating anti-tumour immunity. Here we investigate how stromal cells contribute to the immunosuppressive TME and as a potential therapeutic target to overcome this.

Methods

Using co-culture models of patient-derived TNBC cancer-associated fibroblasts (CAFs) and peripheral blood mononuclear cells (PBMCs) from healthy donors, we applied flow cytometry and single-cell RNA sequencing (scRNAseq) to assess stromal-immune interactions in vitro. A high throughput drug screen was performed to identify novel stromal-targeting drug candidates which could reverse stromal-induced immunosuppression in our coculture models.

Results

TNBC CAFs suppress the proliferative capability of both CD4 and CD8 T cells in vitro. scRNAseq of these co-culture models demonstrate that CAF-cocultured 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 subtype composition from aSMA-positive to aSMA-negative phenotypes. Talabostat treatment in the co-culture models reverses CAF-induced suppression of T cell proliferation.

Conclusions

Talabostat reverses stromal-mediated T cell suppression and is a potential therapeutic strategy to elicit a more effective immune response.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

US Department of Defense grant.

Disclosure

E. Lim: Financial Interests, Institutional, Advisory Board: Gilead, Novartis, Pfizer, Roche, AstraZeneca, MSD, Lilly; Financial Interests, Institutional, Invited Speaker: Roche, Gilead, Novartis, Lilly, AstraZeneca; Financial Interests, Institutional, Research Grant: Pfizer, Novartis; Financial Interests, Institutional, Steering Committee Member: Roche, Lilly, AstraZeneca; Financial Interests, Institutional, Local PI: Novartis, Gilead; Non-Financial Interests, Leadership Role, Scientific Advisory Committee: Breast Cancer Trials Australia; Non-Financial Interests, Leadership Role, Principal Cancer Theme Lead, Faculty of Medicine: University of New South Wales; Non-Financial Interests, Leadership Role, Faculty: Garvan Institute of Medical Research; Non-Financial Interests, Leadership Role, Director Cancer Research: St Vincent's Hospital Sydeny. A. Swarbrick: Financial Interests, Personal and Institutional, Financially Compensated Role, Paid Consultant: Phenomic AI. All other authors have declared no conflicts of interest.