CD73-Mediated Immunosuppression Is Linked to a Specific Fibroblast Population That Paves the Way for New Therapy in Breast Cancer.

Abstract

BACKGROUND:

Cancer-associated fibroblasts (CAF) are heterogeneous with multiple functions in breast cancer. Recently, we identified a specific CAF subpopulation (referred to as CAF-S1), which promotes immunosuppression and immunotherapy resistance.

METHODS AND RESULTS:

Here, by studying a large collection of human samples, we highlight the key function of CD73/NT5E in CAF-S1-mediated immunosuppression in breast cancer. We first reveal that CD73 protein level specifically accumulates in CAF-S1 in breast cancer patients. Interestingly, infiltration of regulatory T lymphocytes (Tregs) is significantly correlated with CD73 expression in stroma but not in epithelium, indicating that CD73 contributes to immunosuppression when expressed in CAF-S1 and not in tumor cells. By performing functional assays based on relevant systems using primary CAF-S1 isolated from patients, we demonstrate that CAF-S1 increase the content in both PD-1+ and CTLA-4+ Tregs. Importantly, the use of a blocking anti-CD73 antibody on CAF-S1 reduces CAF-S1-mediated immunosuppression by preventing expression of these immune checkpoints on Tregs.

CONCLUSIONS:

Our data support the potential clinical benefit of using both anti-CD73 and immune-checkpoint inhibitors in breast cancer patients for inhibiting CAF-S1-mediated immunosuppression and enhancing anti-tumor immune response.

• Authors: Ilaria Magagna, Nicolas Gourdin, Yann Kieffer, Monika Licaj, Rana Mhaidly, Pascale Andre, Ariane Morel, Anne Vincent-Salomon, Carine Paturel, Fatima Mechta-Grigoriou
• Journal: Cancers (Cancers (Basel)) Vol. 13 Issue 23 (Nov 23 2021) ISSN: 2072-6694 [Print] Switzerland
• PMID: 34884993 (Publication Type: Journal Article)