title: Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice.
abstract: The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci.
  
  
  
  We investigated the effects of radiation therapy in p48(Cre);LSL-Kras(G12D) (KC) and p48(Cre);LSLKras(G12D);LSL-Trp53(R172H) (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony-stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2 to 12 Gy and analyzed by flow cytometry.
  
  
  
  Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from radiation treated invasive and preinvasive pancreatic tumors had an immune-suppressive, M2-like phenotype compared with control mice. Pancreata from mice exposed to radiation had fewer CD8(+) T cells than controls, and greater numbers of CD4(+) T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. A neutralizing antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth.
  
  
  
  Radiation treatment causes macrophages murine PDA to acquire an immune-suppressive phenotype and disabled T-cell-mediated anti-tumor responses. MCSF blockade negates this effect, allowing radiation to have increased efficacy in slowing tumor growth.
authors.affiliation: Department of Surgery, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Lena
authors.initials: L
authors.lastname: Seifert
authors.affiliation: Department of Surgery, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Gregor
authors.initials: G
authors.lastname: Werba
authors.affiliation: Department of Surgery, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Shaun
authors.initials: S
authors.lastname: Tiwari
authors.affiliation: Department of Surgery, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Nancy Ngoc
authors.initials: NN
authors.lastname: Giao Ly
authors.affiliation: Department of Radiation Oncology, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Susanna
authors.initials: S
authors.lastname: Nguy
authors.affiliation: Department of Surgery, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Sara
authors.initials: S
authors.lastname: Alothman
authors.affiliation: Department of Surgery, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Dalia
authors.initials: D
authors.lastname: Alqunaibit
authors.affiliation: Department of Surgery, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Antonina
authors.initials: A
authors.lastname: Avanzi
authors.affiliation: Department of Surgery, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Donnele
authors.initials: D
authors.lastname: Daley
authors.affiliation: Department of Surgery, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Rocky
authors.initials: R
authors.lastname: Barilla
authors.affiliation: Department of Surgery, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tippens
authors.affiliation: Department of Surgery, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Torres-Hernandez
authors.affiliation: Department of Surgery, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Mautin
authors.initials: M
authors.lastname: Hundeyin
authors.affiliation: Department of Surgery, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Vishnu R
authors.initials: VR
authors.lastname: Mani
authors.affiliation: Department of Pathology, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Cristina
authors.initials: C
authors.lastname: Hajdu
authors.affiliation: Department of Pathology, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Pellicciotta
authors.affiliation: Department of Radiation Oncology, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Philmo
authors.initials: P
authors.lastname: Oh
authors.affiliation: Department of Radiation Oncology, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Kevin
authors.initials: K
authors.lastname: Du
authors.affiliation: Department of Surgery, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York; Department of Cell Biology, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York. Electronic address: george.miller@nyumc.org.
authors.forename: George
authors.initials: G
authors.lastname: Miller
mesh_terms: D000236:Adenoma / Q000276:immunology* / Q000532:radiotherapy; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology* / Q000532:radiotherapy; D004195:Disease Models, Animal; D008264:Macrophages / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000276:immunology / Q000528:radiation effects; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000532:radiotherapy; D013601:T-Lymphocytes / Q000276:immunology* / Q000528:radiation effects
keywords: Immune Regulation; Pancreas; Pancreatic Cancer; Th2