Introduction: The development of pancreatic ductal adenocarcinoma (PDAC) is closely tied with the immune system. C-C motif chemokine ligands (CCL) were proved to lead to immune recruitment and training. Thus, we reckoned CCL2 to be the kernel of immune suppression in PDAC tissues.
Methods: We compared normal pancreatic tissues with PDAC tissues according to The Cancer Genome Atlas (TCGA) and clinical samples. Flow cytometry was used to identify M-MDSCs. We further demonstrated immune suppression of M-MDSCs according to proliferation rates of CD8+ T cells/CD4+ T cells. Levels of reactive oxygen species (ROS) and Arginase were also tested by flow cytometry, enzyme-linked immunosorbent assay, and western blot analysis. We also analyzed the specific mechanisms by cluster analysis after CCL2 stimulating M-MDSCs.
Results: We found that CCL2 highly increased in PDAC tissues. CCL2 is positively related to CD33 and CD14, markers of monocytic myeloid-derived suppressor cells (M-MDSCs). We have demonstrated that CCL2 recruited M-MDSCs into PDAC tissues both in vitro and in vivo. M-MDSCs recruitment is accompanied by sustained immune suppression. Furthermore, we have found that M-MDSCs impeded T cell proliferation and produced high levels of ROS and Arginase, which can be enhanced by CCL2. Mechanistically, CCL2 stimulated M-MDSCs led to a significant upregulation of genes, a large part of which accumulated in the mitogen-activated protein kinase signaling pathway. Treatment of aloesin, MAPK signaling inhibitor, relieved the associated immunosuppressive phenotype induced by CCL2.
Conclusions: Our study indicates that PDAC cells produced CCL2, which promoted localized M-MDSC recruitment and immune suppression, thereby promoting tumor progression.
Keywords: CCL2; M-MDSCs; immune suppression; pancreatic ductal adenocarcinoma.
© 2021 The Authors. Immunity, Inflammation and Disease John Wiley & Sons Ltd.