163.11 - Protectins Inhibit Estrogen Receptor Negative Breast Cancer Growth in Mice

Franciele Kipper (Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School), Abigail Kelly (Beth Israel Deaconess Medical Center and Harvard Medical School), Eva Rothenberger (Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School), Madeline Duncan (Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School), Charles Serhan (Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital and Harvard Medical School), Dipak Panigrahy (Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School)

Cytotoxic breast cancer therapies reduce tumor burden by killing tumor cells, yet simultaneously generates tumor cell debris. Apoptotic and necrotic debris that are not cleared by the immune system create a pro-inflammatory microenvironment, fueling tumor burden by disrupting the resolution of inflammation. 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 resolvins (Rvs) and protectin conjugates in tissue regeneration (PCTRs), as well as endogenous resolution programs. We have previously reported in mice models that resolvins (e.g. RvD1, RvD2, and RvE1) reduce tumor growth, however the role of protectins in cancer remains unknown. To assess whether stimulating the resolution of inflammation would inhibit breast cancer progression, we utilized protectin (PCTR1) to treat established models of estrogen receptor (ER) positive (EO771) and negative breast cancer (4T1). PCTR1 sharply reduced tumor growth in the EO771 and 4T1 breast cancer models at only nanogram concentrations (15 ng/day) without toxicity when administered alone or in combination with chemotherapy (paclitaxel) and/or immunotherapy (anti-cytotoxic T-lymphocyte-associated protein 4, CTLA4). Notably, PCTR1 inhibited tumor growth in combination with immunotherapy (anti-CTLA4) or immunotherapy plus chemotherapy (paclitaxel) in ER positive (EO771) breast cancer. Also, PCTR1 inhibited ER negative tumor growth (4T1) alone and in combination with paclitaxel and/or anti-CTLA4. Remarkably, PCTR1 alone or in combination with chemotherapy (paclitaxel) reduced gene expression and protein levels of pro-angiogenic factor CXCL12/SDF-1 in the tumor microenvironment. PCTR1 dampened the therapy-induced cytokine storm, by counter-regulating levels of TNF-α, CCL2/MCP-1, CXCL10, CCL5, CXCL13, and IL-1β in vivo. Taken together, we demonstrate that PCTR1, a pro-resolution lipid mediator, inhibits breast cancer progression via debris clearance and counter-regulation of the cytokine storm. The use of protectins to enhance immunotherapy is a novel approach to inhibit breast cancer progression via resolution of inflammation that remains to be evaluated in humans.