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861 Fractionated irradiation activates glioma immune microenvironment and boosts antigen-specific T cell response in experimental gliomas
  1. Nirmeen Elmadany1,2,
  2. Julius Michel2,3,
  3. Jana Sonner3,
  4. Svetlana Ovchinnikova4,
  5. Khwab Sanghvi2,3,
  6. Isabelle Bernhardt2,3,
  7. Xin-Wen Zhang5,
  8. Kristine Jähne3,
  9. Ankita Sati3,
  10. Simon Anders4,
  11. Michael Breckwoldt6,
  12. Michael Platten2,3,7,8,9 and
  13. Katharina Sahm2,3
  1. 1UMM/DKFZ, Heidelberg, Germany
  2. 2Mannheim Center for Translation Neuroscience (MCTN), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
  3. 3DKTK (German Cancer Consortium) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  4. 4Center for Molecular Biology of Heidelberg University (ZMBH), Heidelberg, Germany
  5. 5German Cancer Research Center, Heidelberg, Germany
  6. 6Department of Neuroradiology, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany
  7. 7DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
  8. 8Immune Monitoring Unit, National Center for Tumor Diseases (NCT), Heidelberg, Germany
  9. 9Helmholtz Institute of Translational Oncology (HI-TRON), Mainz, Germany
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Glioblastoma (GBM) is the most aggressive primary brain tumor with a survival rate of 14–16 months. Several ongoing clinical trials employ vaccine, immune checkpoint inhibitors and/or adoptive T cell therapy to treat GBM. However, the impact of irradiation as part of the standard of care on the immune microenvironment and response to immunotherapy is ill-defined.

Methods In the present study, we employed clinically relevant fractionated irradiation (FIR) at a dose of 4x 2 Gy to investigate the response of experimental orthotopic glioma expressing the tumor-associated antigen glycoprotein (gp)100 in immunocompetent syngeneic mice to a gp100 peptide vaccine as well as to adoptively transferred T cells. We employed single cell RNA sequencing to decipher the post-irradiation changes in the GBM immune microenvironment and elucidate the impact FIR on the efficacy of T cell-mediated immunotherapies.

Results FIR boosted the response of orthotopically-implanted GL261 tumors to a gp100 vaccine. Furthermore, FIR enhanced the infiltration of GL261-gp100 gliomas by adoptively-transferred gp100 T cell receptor-transgenic T cells, which also displayed a more activated and less exhausted phenotype post-irradiation. Single cell transcriptomic studies of tumor-infiltrating CD45+ leukocytes revealed that FIR promotes the expression of leukocyte-endothelial adhesion molecules in T cells, and transcripts encoding proinflammatory M1-like genes in tumor-associated microglia and macrophages.

Conclusions Our preclinical findings support the use of FIR with to increase response to T cell-based immunotherapies.

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