title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA.|Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Kristen B
authors.initials: KB
authors.lastname: Long
authors.affiliation: Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA.|Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Whitney L
authors.initials: WL
authors.lastname: Gladney
authors.affiliation: Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA.|Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Graham M
authors.initials: GM
authors.lastname: Tooker
authors.affiliation: Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA.|Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Graham
authors.affiliation: Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Fraietta
authors.affiliation: Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA.|Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Beatty
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D019013:CD40 Antigens / Q000819:agonists; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism*; D004195:Disease Models, Animal; D005355:Fibrosis; D015870:Gene Expression; D007371:Interferon-gamma / Q000378:metabolism*; D064596:Isografts; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*
chemical_list: D000950:Antigens, Ly; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D018932:Chemokine CCL2; C494192:Ly-6C antigen, mouse; D007371:Interferon-gamma; D020782:Matrix Metalloproteinases