IFNγ and CCL2 cooperate to redirect tumor-infiltrating monocytes to degrade fibrosis and enhance chemotherapy efficacy in pancreatic carcinoma

KB Long, WL Gladney, GM Tooker, K Graham… - Cancer discovery, 2016 - AACR
KB Long, WL Gladney, GM Tooker, K Graham, JA Fraietta, GL Beatty
Cancer discovery, 2016AACR
Dense fibrosis and a robust macrophage infiltrate are key therapeutic barriers in pancreatic
ductal adenocarcinoma (PDAC). CD40 activation can circumvent these barriers by inducing
macrophages, originating from peripheral blood monocytes, to deplete fibrosis. The precise
mechanism and therapeutic implications of this antifibrotic activity, though, remain unclear.
Here, we report that IFNγ and CCL2 released systemically in response to a CD40 agonist
cooperate to redirect a subset of Ly6C+ CCR2+ monocytes/macrophages to infiltrate tumors …
Abstract
Dense fibrosis and a robust macrophage infiltrate are key therapeutic barriers in pancreatic ductal adenocarcinoma (PDAC). CD40 activation can circumvent these barriers by inducing macrophages, originating from peripheral blood monocytes, to deplete fibrosis. The precise mechanism and therapeutic implications of this antifibrotic activity, though, remain unclear. Here, we report that IFNγ and CCL2 released systemically in response to a CD40 agonist cooperate to redirect a subset of Ly6C+CCR2+ monocytes/macrophages to infiltrate tumors and deplete fibrosis. Whereas CCL2 is required for Ly6C+ monocyte/macrophage infiltration, IFNγ is necessary for tumor-infiltrating monocytes/macrophages to shift the profile of matrix metalloproteinases (MMP) in tumors, leading to MMP-dependent fibrosis degradation. In addition, MMP13-dependent loss of extracellular matrix components induced by a CD40 agonist increased PDAC sensitivity to chemotherapy. Our findings demonstrate that fibrosis in PDAC is a bidirectional process that can be rapidly altered by manipulating a subset of tumor-infiltrating monocytes, leading to enhanced chemotherapy efficacy.
Significance: We report that CD40 agonists improve chemotherapy efficacy in pancreatic carcinoma by redirecting tumor-infiltrating monocytes/macrophages to induce fibrosis degradation that is dependent on MMPs. These findings provide novel insight into the plasticity of monocytes/macrophages in cancer and their capacity to regulate fibrosis and modulate chemotherapy efficacy in pancreatic carcinoma. Cancer Discov; 6(4); 400–13. ©2016 AACR.
This article is highlighted in the In This Issue feature, p. 331
AACR