Resolvins suppress tumor growth and enhance cancer therapy

• Published in: The Journal of experimental medicine Vol. 215; no. 1; pp. 115 - 140
• Main Authors: Sulciner, Megan L., Serhan, Charles N., Gilligan, Molly M., Mudge, Dayna K., Chang, Jaimie, Gartung, Allison, Lehner, Kristen A., Bielenberg, Diane R., Schmidt, Birgitta, Dalli, Jesmond, Greene, Emily R., Gus-Brautbar, Yael, Piwowarski, Julia, Mammoto, Tadanori, Zurakowski, David, Perretti, Mauro, Sukhatme, Vikas P., Kaipainen, Arja, Kieran, Mark W., Huang, Sui, Panigrahy, Dipak
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 02.01.2018; The Rockefeller University Press
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cancer; Cancer therapies; Carbon tetrachloride; CCL4 protein; Cell Line, Tumor; Cell Proliferation; Chemokines; Chemotherapy; Coinjection; Cytokines; Cytokines - metabolism; Cytotoxicity; Debris; Detritus; Disease Models, Animal; Docosahexaenoic Acids - pharmacology; Humans; Inflammation; Inflammation Mediators - metabolism; Inoculum; Interleukin 6; Interleukin 8; Macrophages; Macrophages - metabolism; Melanoma, Experimental; Mice; Mice, Knockout; Mice, Transgenic; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Phagocytosis; Phosphatidylserine; Phosphatidylserines - metabolism; Tumor Burden; Tumor cells; Tumor necrosis factor-α; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20170681

Cancer therapy reduces tumor burden by killing tumor cells, yet it simultaneously creates tumor cell debris that may stimulate inflammation and tumor growth. Thus, conventional cancer therapy is inherently a double-edged sword. In this study, we show that tumor cells killed by chemotherapy or targeted therapy (“tumor cell debris”) stimulate primary tumor growth when coinjected with a subthreshold (nontumorigenic) inoculum of tumor cells by triggering macrophage proinflammatory cytokine release after phosphatidylserine exposure. Debris-stimulated tumors were inhibited by antiinflammatory and proresolving lipid autacoids, namely resolvin D1 (RvD1), RvD2, or RvE1. These mediators specifically inhibit debris-stimulated cancer progression by enhancing clearance of debris via macrophage phagocytosis in multiple tumor types. Resolvins counterregulate the release of cytokines/chemokines, including TNFα, IL-6, IL-8, CCL4, and CCL5, by human macrophages stimulated with cell debris. These results demonstrate that enhancing endogenous clearance of tumor cell debris is a new therapeutic target that may complement cytotoxic cancer therapies.