Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases
Dipak Panigrahy, … , Charles N. Serhan, Vikas P. Sukhatme
Dipak Panigrahy, … , Charles N. Serhan, Vikas P. Sukhatme
Published June 17, 2019
Citation Information: J Clin Invest. 2019;129(7):2964-2979. https://doi.org/10.1172/JCI127282.
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Research Article Inflammation Oncology

Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases

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 (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.

Authors

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

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Figure 1

Preoperative ketorolac promotes long-term survival and prevents therapy-induced dormancy escape.

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Preoperative ketorolac promotes long-term survival and prevents therapy-...
(A) Preoperative vs. postoperative ketorolac effects on survival after primary tumor resection in a spontaneous LLC metastasis model. n = 5 mice/group. Kaplan-Meier analysis log-rank test, *P < 0.01, control or postoperative ketorolac vs. preoperative ketorolac. (B) H&E staining of lungs from mice at the time of LLC tumor resection (day 0) or from preoperative ketorolac-treated mice at 240 days after resection. Representative micrographs of 10 mice/group. Scale bars: 50 μm. (C–E) Growth of LLC, EL4, or B16F10 in mice treated with preoperative ketorolac or control subjected to laparotomy (day 0, 21, and/or 42 after injection) vs. no laparotomy. n = 10–20 mice/group. Two-way repeated measure mixed-effects ANOVAs for tumor growth rates and 2-tailed Student’s t test for final tumor measurements were used throughout unless specified. (C) *P < 0.001, laparotomy vs. no laparotomy; **P < 0.001, laparotomy and ketorolac vs. laparotomy. (D) *P = 0.009, laparotomy and ketorolac vs. laparotomy; **P < 0.001, laparotomy vs. no laparotomy. (E) *P < 0.05, laparotomy and ketorolac vs. laparotomy; **P < 0.05, laparotomy vs. no laparotomy. (F–H) Growth of LLC, EL4, or CT26 (104 cells) in response to chemotherapy and/or ketorolac. Ketorolac was administered the day before, day of, and day after chemotherapy. Systemic chemotherapy was initiated on day of tumor cell injection. (F) n = 15–28 mice/group. *P < 0.001, cisplatin and ketorolac vs. cisplatin (day 36 after injection). (G) n = 5 mice/group. *P < 0.05, control or vincristine and ketorolac vs. vincristine (day 30 after injection). (H) n = 5 mice/group. *P < 0.01, control or 5-FU and ketorolac vs. 5-FU (day 25 after injection).