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

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          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 anti-fibrotic activity, though, remain unclear. Here, we report that IFN-γ 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, IFN-γ is necessary for tumor-infiltrating monocytes/macrophages to shift the profile of matrix metalloproteinases (MMPs) 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.

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          Author and article information

          Journal
          101561693
          39259
          Cancer Discov
          Cancer Discov
          Cancer discovery
          2159-8274
          2159-8290
          14 April 2016
          19 February 2016
          April 2016
          01 April 2017
          : 6
          : 4
          : 400-413
          Affiliations
          [1 ]Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA
          [2 ]Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
          Author notes
          [* ]To whom correspondence should be addressed: Gregory L. Beatty, MD, PhD, Abramson Cancer Center of the University of Pennsylvania, Smilow Center for Translational Research, Room 8-112, 3400 Civic Center Blvd. Bldg 421, Philadelphia, PA 19104-5156. tele: 215-746-7764. gregory.beatty@ 123456uphs.upenn.edu .
          Article
          PMC4843521 PMC4843521 4843521 nihpa775832
          10.1158/2159-8290.CD-15-1032
          4843521
          26896096
          d9af1085-e1f2-459f-88ed-84e58815aff4
          History
          Categories
          Article

          Monocyte,CCL2,IFN-γ,fibrosis,pancreatic carcinoma
          Monocyte, CCL2, IFN-γ, fibrosis, pancreatic carcinoma

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