Abstract 116: IGFBP2 promotes tumor progression by inducing alternative polarization of macrophages in pancreatic ductal adenocarcinoma

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most lethal and aggressive malignancy. Tumor-associated macrophages (TAMs) mainly represent the M2-like phenotype, with potent immunosuppressive activity, and play a pro-tumor role in nearly all aspects of PDAC biology. Elevated infiltration of M2 TAMs is associated with poor prognosis in PDAC. Insulin-like growth factor binding protein 2 (IGFBP2) is a pleiotropic oncogene that induces PDAC progression and is involved in the regulation of immune responses. Our recent study demonstrated that IGFBP2 potentiates signal transducer and activator of transcription 3 (STAT3) transactivation activities in glioma. Considering the essential role of IGFBP2 in governing tumor progression and immune evasion of PDAC, we hypothesized that IGFBP2 promotes tumor progression by inducing alternatively activated macrophages in PDAC. In this study, immunohistochemical (IHC) staining for human PDAC clinical samples was used to reveal the relationship among IGFBP2 expression, M2 TAM accumulation and patient survival. The function of IGFBP2 in inducing alternative polarization of macrophages and promoting tumor progression in PDAC through the STAT3 pathway were evaluated using in vitro and in vivo assays. Ingenuity pathway and gene set enrichment analyses were used to identify the correlation of IGFBP2 gene expression with all other genes in the genome and enriched pathways associated with IGFBP2 gene expression. Our results provide evidence that IGFBP2 expression is associated with M2 macrophage accumulation in the tumor microenvironment and with poor prognosis in PDAC. IGFBP2 augments the production and secretion of IL-10 through activation of STAT3 in PDAC cells, thus reprogramming the TAMs polarization toward an M2 phenotype and promoting tumor progression. These findings established IGFBP2 as an immune-suppressor in the PDAC microenvironment and suggested a strategy for targeting IGFBP2 to improve PDAC immunotherapy. Citation Format: Longhao Sun, Liang Liu, Weijun Tian, Zhixiang Zhang, Ya'an Kang, Huamin Wang, Jason B. Fleming, Boris C. Pasche, Wei Zhang. IGFBP2 promotes tumor progression by inducing alternative polarization of macrophages in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 116.