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 Article has an altmetric score of 282

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 7

ScRNA-Seq analysis demonstrates an altered immune landscape in response to ketorolac.

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ScRNA-Seq analysis demonstrates an altered immune landscape in response ...
ScRNA-Seq analysis on splenic cells isolated from preoperative ketorolac-treated or control mice 7 days after LLC resection. n = 2 mice/group throughout. (A) 2D visualization of single-cell clusters generated using the tSNE approach from normalized data of 2429 ketorolac-treated and 1864 control splenic cells. Cell clusters were annotated based on expression of established immune cell markers, e.g., T cells (Cd3d+), exhausted T cells (Pdcd1, Ctla4, Lag3, Entpd1, and TIM3), T memory cells (Il7r, Ccr7, Sell, CD44), B cells (Cd19+), dendritic cells (Itgax), and macrophages (Adgre1) (left panel). Chart depicts relative proportions of cells in the clusters from each sample (right panel). (B) Percentage of cells from control and ketorolac-treated mice, per cluster. (C) Preoperative ketorolac effects on the immune landscape of T cells. Feature maps depict the expression of T cell (Cd3d+), exhausted T cell (Pdcd1), and memory T cell (Il7r) markers for each cell cluster on the tSNE map. Cells from ketorolac-treated and control samples are shown as solid dots and triangles, respectively. Bar plots depict the relative proportions of T cell subpopulations in control and ketorolac-treated single-cell profiles. (D) Heatmap depicts the activation or inhibition of key regulators in the control and ketorolac-treated T cell clusters. Regulators were calculated based on Z scores using an upstream regulator analysis module in ingenuity pathways analysis systems.