title: Exclusion of T Cells From Pancreatic Carcinomas in Mice Is Regulated by Ly6C(low) F4/80(+) Extratumoral Macrophages.
abstract: OBJECTIVE
  Immunotherapies that induce T-cell responses have shown efficacy against some solid malignancies in patients and mice, but these have little effect on pancreatic ductal adenocarcinoma (PDAC). We investigated whether the ability of PDAC to evade T-cell responses induced by immunotherapies results from the low level of immunogenicity of tumor cells, the tumor's immunosuppressive mechanisms, or both.
  
  
  METHODS
  Kras(G12D/+);Trp53(R172H/+);Pdx-1-Cre (KPC) mice, which develop spontaneous PDAC, or their littermates (controls) were given subcutaneous injections of a syngeneic KPC-derived PDAC cell line. Mice were then given gemcitabine and an agonist of CD40 to induce tumor-specific immunity mediated by T cells. Some mice were also given clodronate-encapsulated liposomes to deplete macrophages. Tumor growth was monitored. Tumor and spleen tissues were collected and analyzed by histology, flow cytometry, and immunohistochemistry.
  
  
  RESULTS
  Gemcitabine in combination with a CD40 agonist induced T-cell-dependent regression of subcutaneous PDAC in KPC and control mice. In KPC mice given gemcitabine and a CD40 agonist, CD4(+) and CD8(+) T cells infiltrated subcutaneous tumors, but only CD4(+) T cells infiltrated spontaneous pancreatic tumors (not CD8(+) T cells). In mice depleted of Ly6C(low) F4/80(+) extratumoral macrophages, the combination of gemcitabine and a CD40 agonist stimulated infiltration of spontaneous tumors by CD8(+) T cells and induced tumor regression, mediated by CD8(+) T cells.
  
  
  CONCLUSIONS
  Ly6C(low) F4/80(+) macrophages that reside outside of the tumor microenvironment regulate infiltration of T cells into PDAC and establish a site of immune privilege. Strategies to reverse the immune privilege of PDAC, which is regulated by extratumoral macrophages, might increase the efficacy of T-cell immunotherapy for patients with PDAC.
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. Electronic address: gregory.beatty@uphs.upenn.edu.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Beatty
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Family Cancer Research Institute of the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Rafael
authors.initials: R
authors.lastname: Winograd
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Family Cancer Research Institute of the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Evans
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kristen B
authors.initials: KB
authors.lastname: Long
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Santiago L
authors.initials: SL
authors.lastname: Luque
authors.affiliation: 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.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Clendenin
authors.affiliation: 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: Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Dawson M
authors.initials: DM
authors.lastname: Knoblock
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Guirnalda
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; Abramson Family Cancer Research Institute of the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: rhv@exchange.upenn.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D019013:CD40 Antigens / Q000819:agonists; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000276:immunology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D019013:CD40 Antigens; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Lymphocyte; Pancreatic Cancer Treatment; Tolerance; Tumor Microenvironment