Repolarized macrophages, induced by intermediate stereotactic dose radiotherapy and immune checkpoint blockade, contribute to long-term survival in glioma-bearing mice

Alexander M. Stessin, Mariano Guardia Clausi, Zirun Zhao, Hong Lin, Wei Hou, Zhao Jiang, Timothy Q. Duong, Stella E. Tsirka, Samuel Ryu

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Introduction: Glioblastoma multiforme (GBM) is a deadly brain tumor with a short expected median survival, despite current standard-of-care treatment. We explored the combination of intermediate stereotactic dose radiation therapy and immune checkpoint inhibitor therapy as a novel treatment strategy for GBM. Methods: Glioma xenograft-bearing mice were exposed to high dose brain-directed radiation (10 Gy single exposure) as well as mouse anti-PD-1 antibody. The tumor-bearing animals were randomized to four groups: no treatment, radiation alone, anti-PD-1 alone, and radiation + anti-PD-1. Survival was followed, and tumor growth was monitored using MRI. Immunohistochemistry, gene expression arrays, and flow cytometry were used to characterize the treatment-induced effects. Pharmacologic inhibitors of T-lymphocytes, bone marrow derived macrophages, and microglia were used to assess the respective roles of different immune populations in observed treatment effects. Results: We found the combined treatment with high dose radiation and immunotherapy to be highly effective with a 75% complete pathologic response and dramatically improved survival outcomes. We found both CD8+ T-cells and macrophages to be necessary for the full effect of combined therapy, with T lymphocytes appearing to play a role early on and macrophages mediating a later phase of the combined treatment effect. Radiation treatment appeared to trigger macrophage repolarization, increasing M1/M2 ratio. Conclusions: These findings point to a novel immunologic mechanism underlying the interaction between radiotherapy and immunotherapy. They also provide the basis for clinical investigation of immunogenic dose radiation in combination with immune checkpoint blockade as a potential treatment approach for newly diagnosed high grade gliomas.

Original languageEnglish (US)
Pages (from-to)547-555
Number of pages9
JournalJournal of Neuro-Oncology
Volume147
Issue number3
DOIs
StatePublished - May 1 2020
Externally publishedYes

Keywords

  • Glioblastoma
  • Immunotherapy
  • Macrophages
  • Mouse model
  • Radiosurgery
  • T-lymphocytes

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

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