TY - JOUR
T1 - CD200 Immune-Checkpoint Peptide Elicits an Anti-glioma Response Through the DAP10 Signaling Pathway
AU - Ampudia-Mesias, Elisabet
AU - Puerta-Martinez, Francisco
AU - Bridges, Miurel
AU - Zellmer, David
AU - Janeiro, Andrew
AU - Strokes, Matt
AU - Sham, Yuk Y.
AU - Taher, Ayman
AU - Castro, Maria
AU - Moertel, Christopher L.
AU - Pluhar, G. Elizabeth
AU - Olin, Michael R.
N1 - Publisher Copyright:
© 2021, The American Society for Experimental NeuroTherapeutics, Inc.
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
KW - CD200AR
KW - GBM
KW - Immune checkpoints
KW - Immunotherapy
KW - Phase 1
UR - http://www.scopus.com/inward/record.url?scp=85103633064&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85103633064&partnerID=8YFLogxK
U2 - 10.1007/s13311-021-01038-1
DO - 10.1007/s13311-021-01038-1
M3 - Article
C2 - 33829411
AN - SCOPUS:85103633064
SN - 1933-7213
VL - 18
SP - 1980
EP - 1994
JO - Neurotherapeutics
JF - Neurotherapeutics
IS - 3
ER -