Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases

• Type of Material: Article
• Authors: Dipak Panigrahy, Harvard Medical School; Allison Gartung, Harvard Medical School; Jun Yang, University of California Davis; Haixia Yang, Harvard Medical School; Molly M. Gilligan, Harvard Medical School; ML Sulciner, Harvard Medical School; Swati Bhasin, Emory University; Diane R. Bielenberg, Harvard Medical School; Jaimie Chang, Harvard Medical School; Birgitta A. Schmidt, Harvard Medical School; Julia Piwowarski, Harvard Medical School; Anna Fishbein, Harvard Medical School; Dulce Soler-Ferran, Harvard Medical School; Matthew A. Sparks, Duke University; Steven J. Staffa, Harvard Medical School; Bruce D. Hammock, University of California Davis; Mark W. Kieran, Dana Farber Cancer Institute; Sui Huang, Institute for Systems Biology; Manoj Bhasin, Emory University; Charles N. Serhan, Harvard Medical School; Vikas Sukhatme, Emory University
• Language: English
• Date: 2019-07-01
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2019 American Society for Clinical Investigation.
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI127282
• Title of Journal or Parent Work: Journal of Clinical Investigation
• ISSN: 0021-9738
• Volume: 129
• Issue: 7
• Start Page: 2964
• End Page: 2979
• Grant/Funding Information: This work was supported by National Cancer Institute grants RO1 01CA170549 (to DP and CNS), ROCA148633 (to DP), and R01GM038765 (to CNS); Beth Israel Deaconess Medical Center seed funds and a gift from the Sheth family (to VPS); the Credit Unions Kids at Heart Team (to DP); the Stop and Shop Pediatric Brain Tumor Fund (to MWK); the C.J. Buckley Pediatric Brain Tumor Fund (to MWK); Alex’s Lemonade Stand (to MWK); Molly’s Magic Wand for Pediatric Brain Tumors (to MWK); the Markoff Foundation Art-In-Giving Foundation (to MWK); the Kamen Foundation (to MWK); Jared Branfman Sunflowers for Life (to MWK); the Joe Andruzzi Foundation (to MWK); National Institute of Environmental Health Science Superfund Research Program grant P42 ES004699, and National Institute of Environmental Health Science grant RO1 ES002710 (to BDH).
• Keywords: CYCLOOXYGENASE-2 INHIBITORS; ANTIINFLAMMATORY DRUGS; DORMANCY; CELL LUNG-CANCER; Medicine, Research & Experimental; Research & Experimental Medicine; Science & Technology; CHEMOTHERAPY; ASPIRIN; PHASE-II; Life Sciences & Biomedicine; SURGERY; TUMOR-GROWTH; DOUBLE-BLIND
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology; Health Sciences, Pathology

Abstract

Cancer therapy is a double-edged sword, as surgery and chemotherapy can induce an inflammatory/immunosuppressive injury response that promotes dormancy escape and tumor recurrence. We hypothesized that these events could be altered by early blockade of the inflammatory cascade and/or by accelerating the resolution of inflammation. Preoperative, but not postoperative, administration of the nonsteroidal antiinflammatory drug ketorolac and/or resolvins, a family of specialized proresolving autacoid mediators, eliminated micrometastases in multiple tumor-resection models, resulting in long-term survival. Ketorolac unleashed anticancer T cell immunity that was augmented by immune checkpoint blockade, negated by adjuvant chemotherapy, and dependent on inhibition of the COX-1/thromboxane A2 (TXA2) pathway. Preoperative stimulation of inflammation resolution via resolvins (RvD, RvD3, and RvD4) inhibited metastases and induced T cell responses. Ketorolac and resolvins exhibited synergistic antitumor activity and prevented surgery- or chemotherapy-induced dormancy escape. Thus, simultaneously blocking the ensuing proinflammatory response and activating endogenous resolution programs before surgery may eliminate micrometastases and reduce tumor recurrence.