High levels of M-MDSC and low levels of NKp30high NK cells after pancreatic cancer surgery correlate and predict poor survival. A, Forest plots for postoperative survival were generated by log-rank tests where patients were dichotomized on the basis of Youden index for high or low absolute number of M-MDSCs, CD56bright NK cells, CD16+ NK cells, monocytes, lymphocytes, CD8+ T cells, regulatory T cells, CD4+ T cells, DC, neutrophils, or plasma levels of IL6, high expression level of NKp30+ cells among CD16+ (NKp30high CD16+) and CD56bright (NKp30high CD56bright) NK cells one day after surgery or by age or sex. Kaplan–Meier survival comparisons by high (red) or low (blue) absolute numbers of M-MDSC (B) and NKp30high cells among CD16+ NK cells (C) one day after surgery by log-rank test. D, Heat map of correlations (Pearson r, above the diagonal) between immune cell populations and IL6 among patients undergoing pancreatic cancer surgery. P-values corresponding to each correlation are shown below the diagonal. Correlation between absolute numbers of M-MDSC and frequencies of NKp30high cells among CD16+ NK cells at all analyzed timepoints (E), or within the first week after surgery (green dots: pre-op, black dots: 1 day, red dots 3–5 days and orange dots 28 days after surgery; F). Statistics by linear regression. Survival impact of high (red) or low (black) intratumoral NCF2 expression in pancreas cancer samples from the IPEP study (n = 14; G) or the Kaplan–Meier plotter database (n = 852; H), using the best cut-off feature of the portal and log-rank statistics. I, Expression analysis of Single Cell portal PDAC samples showed that the majority of NCF2-expressing cells were confined to a specific immune cell cluster.
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.
