Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases.
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.
Panigrahy, D; Gartung, A; Yang, J; Yang, H; Gilligan, MM; Sulciner, ML; Bhasin, SS; Bielenberg, DR; Chang, J; Schmidt, BA; Piwowarski, J; Fishbein, A; Soler-Ferran, D; Sparks, MA; Staffa, SJ; Sukhatme, V; Hammock, BD; Kieran, MW; Huang, S; Bhasin, M; Serhan, CN; Sukhatme, VP
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