CD200 Immune-Checkpoint Peptide Elicits an Anti-glioma Response Through the DAP10 Signaling Pathway

Elisabet Ampudia-Mesias, Francisco Puerta-Martinez, Miurel Bridges, David Zellmer, Andrew Janeiro, Matt Strokes, Yuk Y. Sham, Ayman Taher, Maria Castro, Christopher L. Moertel, Liz Pluhar, Michael R. Olin

Research output: Contribution to journalArticlepeer-review

Abstract

Numerous therapies aimed at driving an effective anti-glioma response have been employed over the last decade; nevertheless, survival outcomes for patients remain dismal. This may be due to the expression of immune-checkpoint ligands such as PD-L1 by glioblastoma (GBM) cells which interact with their respective receptors on tumor-infiltrating effector T cells curtailing the activation of anti-GBM CD8+ T cell-mediated responses. Therefore, a combinatorial regimen to abolish immunosuppression would provide a powerful therapeutic approach against GBM. We developed a peptide ligand (CD200AR-L) that binds an uncharacterized CD200 immune-checkpoint activation receptor (CD200AR). We sought to test the hypothesis that CD200AR-L/CD200AR binding signals via he DAP10&12 pathways through in vitro studies by analyzing transcription, protein, and phosphorylation, and in vivo loss of function studies using inhibitors to select signaling molecules. We report that CD200AR-L/CD200AR binding induces an initial activation of the DAP10&12 pathways followed by a decrease in activity within 30 min, followed by reactivation via a positive feedback loop. Further in vivo studies using DAP10&12KO mice revealed that DAP10, but not DAP12, is required for tumor control. When we combined CD200AR-L with an immune-stimulatory gene therapy, in an intracranial GBM model in vivo, we observed increased median survival, and long-term survivors. These studies are the first to characterize the signaling pathway used by the CD200AR, demonstrating a novel strategy for modulating immune checkpoints for immunotherapy currently being analyzed in a phase I adult trial.

Original languageEnglish (US)
JournalNeurotherapeutics
DOIs
StateAccepted/In press - 2021

Bibliographical note

Publisher Copyright:
© 2021, The American Society for Experimental NeuroTherapeutics, Inc.

Keywords

  • CD200AR
  • GBM
  • Immune checkpoints
  • Immunotherapy
  • Phase 1

PubMed: MeSH publication types

  • Journal Article

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