Abstract 3232: NF-κB regulates suppression of macrophage activity during tumor initiation

Abstract

Abstract Constitutive activation of NF-κB is characteristic of most cancer cells. However, how NF-κB functions during tumor initiation is not well established. Recent findings from our laboratory showed that one mechanism by which NF-κB functions to promote tumor initiation is by suppressing immune surveillance. Here we investigated how this occurs. Initiating tumors are characterized by a massive infiltration of immune cells, especially macrophages that exhibit anti-tumor activity through the secretion of pro-apoptotic factors like tumor necrosis factor (TNF) and nitric oxide (NO). Using co-culture assays with conditioned media from Ras transformed tumor cells in the presence of NF-κB, we find that the tumor cells are able to protect themselves from the pro-apoptotic activity of the macrophages by secreting a neutralizing factor. RNA sequencing analysis identified this factor as macrophage inhibitory cytokine-1 (MIC-1)/ growth and differentiation factor-15 (GDF-15). Our results show that MIC-1/GDF-15 is a direct transcriptional target of NF-κB. Furthermore, xenografts in SCID mice show delayed tumor initiation in p65+/+ Ras tumor cells that are depleted for MIC-1/GDF-15 compared to wild type p65+/+ Ras tumor cells. Moreover, we find that MIC-1/GDF-15 inactivates macrophages directly by suppressing their ability to produce TNF and NO. This suppression occurs through the inhibition of NF-κB signaling in the macrophages. Interestingly, expression of MIC-1/GDF-15 is increased in patients with pancreatic ductal adenocarcinoma. In the pancreatic cancer cell line, Panc02, we show that knocking down MIC-1/GDF-15 prevents macrophage inhibition thereby increasing their sensitivity to macrophage-mediated killing both in vitro and in vivo. Thus, NF-κB functions during pancreatic cancer initiation to suppress the anti-tumor activity of infiltrating macrophages by regulating the expression of MIC-1/GDF-15. Citation Format: Nivedita Ratnam, David Wang, Denis Guttridge. NF-κB regulates suppression of macrophage activity during tumor initiation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3232.