Journal Article

Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases

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

2019

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adjuvant chemotherapy / Analysis / Animals / Anti-inflammatory agents / Antineoplastic agents / Antitumor activity / Aspirin / Biomarkers / Biomedical research / Breast cancer / Cancer / Cancer metastasis / Cancer surgery / Cancer therapies / Cancer treatment / Chemotherapy / Clopidogrel / Cyclooxygenase-1 / Cytokines / Development and progression / Docosahexaenoic Acids - pharmacology / Dormancy / Health aspects / Immune checkpoint / Immunity, Cellular - drug effects / Inflammation / Ketorolac / Ketorolac - pharmacology / Lung cancer / Lymphocytes T / Male / Metastases / Metastasis / Mice / Mice, Knockout / Neoplasm Metastasis / Neoplasm Recurrence, Local - metabolism / Neoplasm Recurrence, Local - pathology / Neoplasm Recurrence, Local - prevention & control / Neoplasms, Experimental - metabolism / Neoplasms, Experimental - pathology / Neoplasms, Experimental - therapy / Preoperative Care / Recurrence (Disease) / Surgery / T cells / T-Lymphocytes - metabolism / T-Lymphocytes - pathology / Thromboxane A2 / Tumors / Vincristine