IFNγ and CCL2 Cooperate to Redirect Tumor-Infiltrating Monocytes to Degrade Fibrosis and Enhance Chemotherapy Efficacy in Pancreatic Carcinoma
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2016
- Source ID
- 10.1158/2159-8290.cd-15-1032
Entities
People
- Graham M. Tooker
- Gregory L Beatty
- Joseph A. Fraietta
- Kathleen Graham
- Kristen B. Long
- Whitney L. Gladney
Organizations
- Damon Runyon Cancer Research Foundation
- Doris Duke Charitable Foundation
- National Cancer Institute
- National Institutes of Health
- United States Department of Defense
- University of Pennsylvania
- W. W. Smith Charitable Trust