The Journal of clinical investigation
Animals; Docosahexaenoic Acids; Immunity, Cellular; Ketorolac; Male; Mice; Mice, Knockout; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms, Experimental; Preoperative Care; T-Lymphocytes
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.
Institute for Systems Biology
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; and Sukhatme, Vikas P, "Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases." (2019). Articles, Abstracts, and Reports. 3181.