Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases

Panigrahy, Dipak
Gartung, Allison
Yang, Jun
Yang, Haixia
Gilligan, Molly M.
Sulciner, Megan L.
Bhasin, Swati S.
Bielenberg, Diane R.
Chang, Jaimie
Schmidt, Birgitta A.
Piwowarski, Julia
Fishbein, Anna
Soler-Ferran, Dulce
Sparks, Matthew A.
Staffa, Steven J.
Sukhatme, Vidula
Hammock, Bruce D.
Kieran, Mark W.
Huang, Sui
Bhasin, Manoj
Serhan, Charles N.
Sukhatme, Vikas P.

¹Center for Vascular Biology Research,
²Department of Pathology, and
³Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
⁴Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, California, USA.
⁵Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
⁶Vascular Biology Program and
⁷Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁸Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, USA.
⁹Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁰GlobalCures Inc., Newton, Massachusetts, USA.
¹¹Division of Pediatric Oncology, Dana-Farber Cancer Institute, and
¹²Department of Pediatric Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹³Institute for Systems Biology, Seattle, Washington, USA.
¹⁴Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁵Department of Medicine and Center for Affordable Medical Innovation, Emory University School of Medicine, Atlanta, Georgia, USA.

Address correspondence to: Dipak Panigrahy, 99 Brookline Avenue, RN220, Boston, Massachusetts 02215, USA. Phone: 617.667.8202; Email: [email protected]. Or to Charles N. Serhan, 60 Fenwood Road, Room 3012, Boston, Massachusetts 02115, USA. Phone: 617.525.5001; Email: [email protected]. Or to Vikas P. Sukhatme, 100 Woodruff Circle, Suite 423, Atlanta, Georgia 30322, USA. Phone: 404.727.5631; Email: [email protected].

Authorship note: DP, AG, and JY contributed equally to this work.

Received January 11, 2019

Accepted April 17, 2019

Journal of Clinical Investigation 129(7):p 2964-2979, July 1, 2019. | DOI: 10.1172/JCI127282

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 (RvD2, 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.