title: Tumor-Derived CCL2 Mediates Resistance to Radiotherapy in Pancreatic Ductal Adenocarcinoma.
abstract: OBJECTIVE
  Local tumor growth is a major cause of morbidity and mortality in nearly 30% of patients with pancreatic ductal adenocarcinoma (PDAC). Radiotherapy is commonly used for local disease control in PDAC, but its efficacy is limited. We studied the impact of selectively intervening on radiotherapy-induced inflammation as an approach to overcome resistance to radiotherapy in PDAC.
  
  
  METHODS
  PDAC cell lines derived from primary pancreatic tumors arising spontaneously in KrasLSL-G12D/+;Trp53LSL-R172H/+;Pdx-1 Cre mice were implanted into syngeneic mice and tumors were focally irradiated using the Small Animal Radiation Research Platform (SARRP). We determined the impact of depleting T cells and Ly6C+monocytes as well as inhibiting the chemokine CCL2 on radiotherapy efficacy. Tumors were analyzed by flow cytometry and IHC to detect changes in leukocyte infiltration, tumor viability, and vascularity. Assays were performed on tumor tissues to detect cytokines and gene expression.
  
  
  RESULTS
  Ablative radiotherapy alone had minimal impact on PDAC growth but led to a significant increase in CCL2 production by tumor cells and recruitment of Ly6C+CCR2+monocytes. A neutralizing anti-CCL2 antibody selectively inhibited radiotherapy-dependent recruitment of monocytes/macrophages and delayed tumor growth but only in combination with radiotherapy (P < 0.001). This antitumor effect was associated with decreased tumor proliferation and vascularity. Genetic deletion of CCL2 in PDAC cells also improved radiotherapy efficacy.
  
  
  CONCLUSIONS
  PDAC responds to radiotherapy by producing CCL2, which recruits Ly6C+CCR2+monocytes to support tumor proliferation and neovascularization after radiotherapy. Disrupting the CCL2-CCR2 axis in combination with radiotherapy holds promise for improving radiotherapy efficacy in PDAC. Clin Cancer Res; 23(1); 137-48. ©2016 AACR.
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Anusha
authors.initials: A
authors.lastname: Kalbasi
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.|Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Chad
authors.initials: C
authors.lastname: Komar
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.|Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Graham M
authors.initials: GM
authors.lastname: Tooker
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.|Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Mingen
authors.initials: M
authors.lastname: Liu
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.|Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jae W
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.|Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Whitney L
authors.initials: WL
authors.lastname: Gladney
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Edgar
authors.initials: E
authors.lastname: Ben-Josef
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. gregory.beatty@uphs.upenn.edu.|Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Beatty
mesh_terms: D000818:Animals; D015415:Biomarkers; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism*; D002633:Chemotaxis; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics*; D047368:Tumor Burden / Q000528:radiation effects; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D015415:Biomarkers; D018932:Chemokine CCL2; D016207:Cytokines; D018836:Inflammation Mediators