Glioblastoma extracellular vesicles modulate immune PD-L1 expression in accessory macrophages upon radiotherapy
Markus W. Schweiger,
Zohreh Amoozgar,
Pierre Repiton,
Robert Morris,
Semer Maksoud,
Michael Hla,
Eric Zaniewski,
David P. Noske,
Wilhelm Haas,
Koen Breyne,
Bakhos A. Tannous
Affiliations
Markus W. Schweiger
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA; Neuroscience Program, Harvard Medical School, Boston, MA 02129, USA; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Neurosurgery, 1081 HV Amsterdam, the Netherlands; Cancer Center Amsterdam, Brain Tumor Center and Liquid Biopsy Center, 1081 HV Amsterdam, the Netherlands
Zohreh Amoozgar
Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Pierre Repiton
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA; Neuroscience Program, Harvard Medical School, Boston, MA 02129, USA; Section of Pharmaceutical Sciences, Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1205 Geneva, Switzerland
Robert Morris
Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA
Semer Maksoud
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA; Neuroscience Program, Harvard Medical School, Boston, MA 02129, USA
Michael Hla
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA; Neuroscience Program, Harvard Medical School, Boston, MA 02129, USA
Eric Zaniewski
Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA
David P. Noske
Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Neurosurgery, 1081 HV Amsterdam, the Netherlands; Cancer Center Amsterdam, Brain Tumor Center and Liquid Biopsy Center, 1081 HV Amsterdam, the Netherlands
Wilhelm Haas
Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA
Koen Breyne
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA; Neuroscience Program, Harvard Medical School, Boston, MA 02129, USA; Corresponding author
Bakhos A. Tannous
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA; Neuroscience Program, Harvard Medical School, Boston, MA 02129, USA; Corresponding author
Summary: Glioblastoma (GBM) is the most aggressive brain tumor, presenting major challenges due to limited treatment options. Standard care includes radiation therapy (RT) to curb tumor growth and alleviate symptoms, but its impact on GBM is limited. In this study, we investigated the effect of RT on immune suppression and whether extracellular vesicles (EVs) originating from GBM and taken up by the tumor microenvironment (TME) contribute to the induced therapeutic resistance.We observed that (1) ionizing radiation increases immune-suppressive markers on GBM cells, (2) macrophages exacerbate immune suppression in the TME by increasing PD-L1 in response to EVs derived from GBM cells which is further modulated by RT, and (3) RT increases CD206-positive macrophages which have the most potential in inducing a pro-oncogenic environment due to their increased uptake of tumor-derived EVs.In conclusion, RT affects GBM resistance by immuno-modulating EVs taken up by myeloid cells in the TME.
