Title
Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases.
Document Type
Article
Publication Date
6-17-2019
Publication Title
The Journal of clinical investigation
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.
Department
Institute for Systems Biology
Department
Surgery
Recommended Citation
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. 1733.
https://digitalcommons.providence.org/publications/1733