Abstract A64: Commensal dysbiosis alters the tumor microenvironment in breast cancer and diminishes efficacy of PD-L1 blockade

Abstract

Abstract Hormone receptor-positive (HR+) breast cancer is largely nonresponsive to checkpoint blockade therapy. Alterations in the composition of commensal microbes influence the systemic immune environment and can diminish responses to checkpoint blockade. Reduced diversity of commensal microbes, known as dysbiosis, has been demonstrated in women with advanced breast cancer and is associated with increases of systemic immunosuppressive mediators that are detrimental in the context of breast cancer, including prostaglandin E2 (PGE2). This bioactive lipid promotes the differentiation of myeloid cells that can exert immunosuppressive effects in the tumor microenvironment. In a novel, clinically relevant model of HR+ breast cancer, PD-L1 blockade was effective when combined with meloxicam, a drug that targets PGE2 synthesis through inhibition of COX-2. However, this combination therapy was ineffective in mice that were previously treated with antibiotics to induce dysbiosis, despite elevated levels of PGE2 in these animals. Commensal dysbiosis altered the cellular composition within the tumor microenvironment, promoting the recruitment of suppressive myeloid populations and driving significant and irreversible T-cell dysfunction. Importantly, COX-1 also regulates PGE2 synthesis, and mammary glands from dysbiotic mice showed significantly enhanced COX-1 activity, suggesting a previously unknown mechanism by which dysbiosis can affect breast tumor progression and resistance to therapy. Targeting COX-1-mediated PGE2 synthesis resulted in decreased tumor burden only in dysbiotic mice, suggesting that dysbiosis-induced COX-1-mediated tissue inflammation is sufficient to drive immune suppression in advanced breast cancer. This work provides important insights on the premalignant environment in the breast, enhances our understanding of the mechanisms driving failure of PD-1/PD-L1 blockade, and identifies novel targets that may provide clinical benefit for women with breast cancer. Citation Format: Claire Buchta Rosean, Raegan Bostic, Tzu Yu Feng, Melanie R. Rutkowski. Commensal dysbiosis alters the tumor microenvironment in breast cancer and diminishes efficacy of PD-L1 blockade [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A64.