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posted on 2024-04-25, 14:20 authored by Hanna Grauers Wiktorin, Ebru Aydin, Roberta Kiffin, Caroline Vilhav, Johan Bourghardt Fagman, Mustafa Kaya, Sanchari Paul, Beatrice Westman, Svein Olav Bratlie, Peter Naredi, Kristoffer Hellstrand, Anna Martner NOX2 inhibition prevents surgery-induced metastasis in a murine model. A, Schematic outline of the experimental model of surgery-induced metastasis. Blood samples were collected from naïve (Ctrl) and sponge-bearing (Inf) WT and NOX2-KO mice 1 week after a surgical procedure (sponge implantation). A group of WT mice received intraperitoneal injections with histamine dihydrochloride (WT HDC) every other day starting one day before surgery and continuing until 3 days after tumor cell challenge. Frequency of CD11b+Ly6C+M-MDSC (B) and intracellular ROS levels in M-MDSC (C) were measured by flow cytometry. At 8 days postsurgery, mice were intravenously inoculated with B16F10 cells. D, Metastatic lesions in lungs were enumerated 19–21 days after tumor cell challenge. Differences in inflammatory monocytes, DCFDA levels, and tumor numbers in vivo were calculated using one-way ANOVA following Holm-Šídák multiple comparisons test. The frequency of M-MDSC and number of metastatic foci was evaluated in four independent experiments for WT mice with or without surgery-induced inflammation, and in two experiments for KO mice and HDC treated mice. DCFDA levels of M-MDSC were measured in three independent experiments for WT mice, two experiments for KO mice, and one experiment for HDC-treated mice. In each experiment, 4–5 mice per group were included. Fold change was calculated by dividing raw data with the mean of raw data in the WT mice control group in each experiment. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001.
Funding
Vetenskapsrådet (VR)
Cancerfonden (Swedish Cancer Society)
Stiftelsen Assar Gabrielssons Fond (AG Fond)
Stiftelserna Wilhelm och Martina Lundgrens (Wilhelm and Martina Lundgren Foundation)
Sahlgrenska University Hospitals Research Foundations
History
ARTICLE ABSTRACT
Preclinical studies imply that surgery triggers inflammation that may entail tumor outgrowth and metastasis. The potential impact of surgery-induced inflammation in human pancreatic cancer is insufficiently explored. This study included 17 patients with periampullary cancer [pancreatic ductal adenocarcinoma (PDAC) n = 14, ampullary carcinoma n = 2, cholangiocarcinoma n = 1] undergoing major pancreatic cancer surgery with curative intent. We analyzed the potential impact of preoperative and postoperative immune phenotypes and function on postoperative survival with >30 months follow-up. The surgery entailed prompt expansion of monocytic myeloid-derived suppressor cells (M-MDSC) that generated NOX2-derived reactive oxygen species (ROS). Strong induction of immunosuppressive M-MDSC after surgery predicted poor postoperative survival and coincided with reduced functionality of circulating natural killer (NK) cells. The negative impact of surgery-induced M-MDSC on survival remained significant in separate analysis of patients with PDAC. M-MDSC–like cells isolated from patients after surgery significantly suppressed NK cell function ex vivo, which was reversed by inhibition of NOX2-derived ROS. High NOX2 subunit expression within resected tumors from patients with PDAC correlated with poor survival whereas high expression of markers of cytotoxic cells associated with longer survival. The surgery-induced myeloid inflammation was recapitulated in vivo in a murine model of NK cell–dependent metastasis. Surgical stress thus induced systemic accumulation of M-MDSC–like cells and promoted metastasis of NK cell–sensitive tumor cells. Genetic or pharmacologic suppression of NOX2 reduced surgery-induced inflammation and distant metastasis in this model. We propose that NOX2-derived ROS generated by surgery-induced M-MDSC may be targeted for improved outcome after pancreatic cancer surgery.
Pancreatic cancer surgery triggered pronounced accumulation of NOX2+ myeloid-derived suppressor cells that inhibited NK cell function and negatively prognosticated postoperative patient survival. We propose the targeting of M-MDSC as a conceivable strategy to reduce postoperative immunosuppression in pancreatic cancer.
