Pancreatic cancer surgery triggers inflammation and expansion of M-MDSC. A, Flow chart of included IPEP study participants. B, Study design and available samples. Absolute numbers of neutrophils (C), monocytes (D), and lymphocytes (E) in patients undergoing surgery for periampullary cancer with whole blood samples (differential counts) analyzed before (pre-op) and 1, 3–5 and 28 days after pancreatic cancer surgery (day 1, days 3–5, and day 28, respectively; N = 17 for pre-op, N = 16 for day 1, N = 15 for days 3–5, N = 11 for day 28). F, Plasma levels of IL6 in healthy donors (HD) and in pre- and post-op samples from patients (N = 16 for pre-op and for day 1, N = 15 for days 3–5, N = 9 for day 28, N = 6 for HD). G–I, CD14+HLADRlow M-MDSC in peripheral blood of healthy donors and patients before and after surgery analyzed by flow cytometry. G, Representative FACS plot of the frequency of CD14+HLADRlow cells among CD14+ cells. Absolute numbers (H) and frequencies (I) of M-MDSC (N = 17 for pre-op, N = 16 for day 1 and days 3–5, N = 10 for day 28, N = 12 for HD). J, M-MDSC levels of ROS as measured by DCFDA MFI (N = 16 for pre-op, for day 1 and for days 3–5, N = 10 for day 28, N = 12 for HD). Preoperative and postoperative samples were compared using mixed-effects analysis followed by Šídák multiple comparison test (P-values indicated by *). HD and cancer samples were compared using Kruskal–Wallis test followed by Dunn multiple comparison test (P-values indicated by #). */#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
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.
