Related Experiment Video
Updated: Oct 6, 2025
Intranasal Delivery of Therapeutic Stem Cells to Glioblastoma in a Mouse Model
Published on: June 4, 2017
NOTCH-Induced MDSC Recruitment after oHSV Virotherapy in CNS Cancer Models Modulates Antitumor Immunotherapy
Yoshihiro Otani1, Ji Young Yoo1, Cole T Lewis1
1Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas.
Purpose:
Oncolytic herpes simplex virus-1 (oHSV) infection of brain tumors activates NOTCH, however the consequences of NOTCH on oHSV-induced immunotherapy is largely unknown. Here we evaluated the impact of NOTCH blockade on virus-induced immunotherapy.
Experimental Design:
RNA sequencing (RNA-seq), TCGA data analysis, flow cytometry, Luminex- and ELISA-based assays, brain tumor animal models, and serum analysis of patients with recurrent glioblastoma (GBM) treated with oHSV was used to evaluate the effect of NOTCH signaling on virus-induced immunotherapy.
Results:
TCGA data analysis of patients with grade IV glioma and oHSV treatment of experimental brain tumors in mice showed that NOTCH signaling significantly correlated with a higher myeloid cell infiltration. Immunofluorescence staining and RNA-seq uncovered a significant induction of Jag1 (NOTCH ligand) expression in infiltrating myeloid cells upon oHSV infection. Jag1-expressing macrophages further spread NOTCH activation in the tumor microenvironment (TME). NOTCH-activated macrophages increased the secretion of CCL2, which further amplified myeloid-derived suppressor cells. CCL2 and IL10 induction was also observed in serum of patients with recurrent GBM treated with oHSV (rQnestin34.5; NCT03152318). Pharmacologic blockade of NOTCH signaling rescued the oHSV-induced immunosuppressive TME and activated a CD8-dependent antitumor memory response, resulting in a therapeutic benefit.
Conclusions:
NOTCH-induced immunosuppressive myeloid cell recruitment limited antitumor immunity. Translationally, these findings support the use of NOTCH inhibition in conjunction with oHSV therapy.
Insights
Blocking NOTCH signaling enhances oncolytic herpes simplex virus-1 (oHSV) immunotherapy for brain tumors by reducing immunosuppressive myeloid cells. This approach activates a CD8-dependent antitumor response, improving therapeutic outcomes.
Area of Science:
- Oncology
- Immunology
- Virology
Background:
- Oncolytic herpes simplex virus-1 (oHSV) therapy for brain tumors activates NOTCH signaling.
- The precise role of NOTCH in oHSV-induced immunotherapy remains unclear.
Purpose of the Study:
- To investigate the impact of NOTCH pathway blockade on oHSV-mediated anti-tumor immunotherapy.
- To determine how NOTCH signaling influences the tumor microenvironment during oHSV treatment.
Main Methods:
- Utilized RNA sequencing, TCGA data analysis, flow cytometry, Luminex and ELISA assays.
- Employed brain tumor animal models and analyzed patient serum from recurrent glioblastoma treated with oHSV.
Main Results:
- NOTCH signaling correlated with increased myeloid cell infiltration in glioma.
- oHSV infection induced Jag1 expression in myeloid cells, promoting NOTCH activation and immunosuppression via CCL2 and IL10.
- NOTCH blockade reversed the immunosuppressive tumor microenvironment and initiated a CD8+ T cell-mediated anti-tumor response.
Conclusions:
- NOTCH-induced immunosuppressive myeloid cell recruitment hinders anti-tumor immunity.
- Combining NOTCH inhibition with oHSV therapy shows translational potential for improved brain tumor treatment.
Related Concept Videos
01:27Tumor Immunotherapy
03:14Notch Signaling Pathway
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...