Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Lena Seifert - , Klinik und Poliklinik für Viszeral- Thorax- und Gefäßchirurgie, Nationales Centrum für Tumorerkrankungen Dresden, S. Arthur Localio Laboratory, New York University (Autor:in)
  • Gregor Werba - , New York University (Autor:in)
  • Shaun Tiwari - , New York University (Autor:in)
  • Nancy Ngoc Giao Ly - , New York University (Autor:in)
  • Susanna Nguy - , New York University (Autor:in)
  • Sara Alothman - , New York University (Autor:in)
  • Dalia Alqunaibit - , New York University (Autor:in)
  • Antonina Avanzi - , New York University (Autor:in)
  • Donnele Daley - , New York University (Autor:in)
  • Rocky Barilla - , New York University (Autor:in)
  • Daniel Tippens - , New York University (Autor:in)
  • Alejandro Torres-Hernandez - , New York University (Autor:in)
  • Mautin Hundeyin - , New York University (Autor:in)
  • Vishnu R Mani - , New York University (Autor:in)
  • Cristina Hajdu - , New York University (Autor:in)
  • Ilenia Pellicciotta - , New York University (Autor:in)
  • Philmo Oh - , New York University (Autor:in)
  • Kevin Du - , New York University (Autor:in)
  • George Miller - , New York University (Autor:in)

Abstract

BACKGROUND & AIMS: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.

Details

OriginalspracheEnglisch
Seiten (von - bis)1659-1672.e5
FachzeitschriftGastroenterology
Jahrgang150
Ausgabenummer7
PublikationsstatusVeröffentlicht - Juni 2016
Peer-Review-StatusJa

Externe IDs

PubMedCentral PMC4909514
Scopus 84975861191

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • Adenoma/immunology, Animals, Carcinoma, Pancreatic Ductal/immunology, Disease Models, Animal, Macrophages/radiation effects, Mice, Mice, Inbred C57BL, Pancreas/immunology, Pancreatic Neoplasms/immunology, T-Lymphocytes/immunology