Abstract 1329: Maresins prevent breast cancer dormancy escape via resolution of inflammation

Abstract

Abstract Cytotoxic cancer therapies reduce tumor burden by killing tumor cells. However, the resulting apoptotic and necrotic cell bodies (tumor cell “debris”) may stimulate tumor initiation and progression by disrupting the resolution of inflammation. Thus, chemotherapy and anti-estrogen breast cancer therapy, including tamoxifen, may be a double-edged sword. A paradigm shift is emerging in understanding the resolution of inflammation as an active biochemical process with the discovery of novel specialized pro-resolving lipid autocoid mediators (SPMs), such as maresins and endogenous resolution programs. Despite approaches to block systemic inflammation, there are no current “pro-resolving” therapies in cancer. To determine whether debris stimulates breast cancer growth, we utilized tumor dormancy models with a subthreshold (nontumorigenic) inoculum of tumor cells. We demonstrated that breast tumor “debris” generated by cytotoxic anti-estrogen therapy (tamoxifen or fulvestrant) or chemotherapy (eribulin) stimulates dormancy escape by triggering a macrophage-derived pro-inflammatory and pro-angiogenic “cytokine storm”. Thus, tumor cell debris is a critical pro-tumorigenic factor in breast cancer initiation and progression. To assess whether stimulating the clearance of debris would suppress breast cancer progression, we utilized the SPMs maresin 1 (MaR1) and maresin conjugates in tissue regeneration (MCTR1, MCTR2). Each maresin (MaR1, MCTR1 and MCTR2) sharply reduced tumor growth in both debris-stimulated and spontaneous (e.g. MMTV-PyMT) breast cancer models at nanogram concentrations (15 ng/day) without toxicity. Notably, maresins enhanced immunotherapy (anti-CTLA4) to induce tumor regression in estrogen receptor (ER) positive (EO771) and inhibit ER negative tumor growth (4T1). Maresins stimulated macrophage phagocytosis of therapy (fulvestrant and tamoxifen)-generated breast cancer debris at only nanomolar concentrations (0.1 - 10 nM). Remarkably, maresins alone or in combination with chemotherapy (paclitaxel) reduced levels of pro-angiogenic factors (e.g. CXCL12/SDF-1) in the tumor microenvironment and decreased microvessel density/size, thereby inhibiting tumor angiogenesis. Maresins dampened the therapy-induced cytokine storm, by reducing levels of TNF-α, MIP-2/CXCL2, CCL2/MCP-1, IL-1ra/IL-1F3, CCL5, CXCL13, Serpin E1/PAI-1, IL-1β and G-CSF both in vitro in debris-stimulated macrophages and in vivo in plasma and tumor tissue. Stimulating the resolution of inflammation via pro-resolution lipid mediators to enhance immunotherapy is a novel host-centric therapeutic approach to prevent breast cancer initiation, dormancy escape and tumor progression via debris clearance and counter-regulation of the cytokine storm. Altogether, the maresin pathway mediators may represent a new therapeutic approach to stimulate the resolution of inflammation in breast cancer. Citation Format: Franciele Cristina Kipper, Jianjun Deng, Eva Rothenberger, Abigail Kelly, Madeline Duncan, Sui Huang, Charles N. Serhan, Dipak Panigrahy. Maresins prevent breast cancer dormancy escape via resolution of inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1329.