Increasing glioma-associated monocytes leads to increased intratumoral and systemic myeloid-derived suppressor cells in a murine model

Michael Chae, Timothy E. Peterson, Alexis Balgeman, Selby Chen, Lei Zhang, Danielle N. Renner, Aaron J. Johnson, Ian F Parney

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Background Patients with glioblastoma multiforme (GBM) exhibit marked intratumoral and systemic immunosuppression. GBM is heavily infiltrated with monocytic cells. Monocytes contacting GBM cells develop features of immunosuppressive myeloid-derived suppressor cells (MDSCs), which are elevated in GBM patients. Therefore, we hypothesized that circulating MDSC levels could be raised in vivo by increasing glioma-associated macrophages. Methods GL261-luciferase glioma was implanted intracranially in C57BL/6 mice with or without additional normal syngeneic CD11b+ monocytes. Tumor growth and intratumoral and systemic MDSC (CD11b+/Gr-1+) levels were determined. Green fluorescent protein (GFP)-transgenic monocytes were coinjected intracranially with GL261-luciferase cells. GFP+ cell frequency among splenic and bone marrow MDSCs was determined. Impact of increased MDSC's on spontaneous immune responses to tumor cells expressing a model antigen (ovalbumin [OVA]) was determined. Results Tumors grew faster and MDSC's were increased in tumor, spleen, and bone marrow in mice receiving GL261-Luc plus monocytes. Many (30%-50%) systemic MDSC's were GFP+ in mice receiving intracranial tumor plus GFP-transgenic monocytes, suggesting that they originated from glioma-associated monocytes. Tumor-infiltrating OVA-specific CD8+ T cells were markedly reduced in mice receiving GL261-OVA and monocytes compared with mice receiving GL261-OVA alone. Conclusions Increasing glioma-associated macrophages in intracranial GL261 glioma decreases survival and markedly increases intratumoral and systemic MDSC's, many of which originate directly from glioma-associated macrophages. This is associated with decreased spontaneous immune responses to a model antigen. To our knowledge, this is the first evidence in cancer that systemic MDSC's can arise directly from normal monocytes that have undergone intratumoral immunosuppressive education.

Original languageEnglish (US)
Pages (from-to)978-991
Number of pages14
JournalNeuro-Oncology
Volume17
Issue number7
DOIs
StatePublished - Jul 1 2015

    Fingerprint

Keywords

  • GL261
  • Glioma
  • immunosuppression
  • myeloid-derived suppressor cell
  • tumor-associated macrophage.

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Cite this