NOTCH-Induced MDSC Recruitment after oHSV Virotherapy in CNS Cancer Models Modulates Antitumor Immunotherapy

Authors

Yoshihiro Otani
Ji Young Yoo
Cole T Lewis
Samantha Chao
Jessica Swanner
Toshihiko Shimizu
Jin Muk Kang
Sara A Murphy
Kimberly Rivera-Caraballo
Bangxing Hong
Joseph C Glorioso
Hiroshi Nakashima
Sean E Lawler
Yeshavanth Banasavadi-Siddegowda
John D Heiss
Yuanqing Yan
Guangsheng Pei
Michael A Caligiuri
Zhongming Zhao
E Antonio Chiocca
Jianhua Yu
Balveen Kaur

Publication Date

4-1-2022

Journal

Clinical Cancer Research

Abstract

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.

Keywords

Animals, Cell Line, Tumor, Glioblastoma, Humans, Immunotherapy, Mice, Myeloid-Derived Suppressor Cells, Neoplasm Recurrence, Local, Oncolytic Virotherapy, Oncolytic Viruses, Simplexvirus, Tumor Microenvironment, Xenograft Model Antitumor Assays, Myeloid derived suppressor cells, oncolytic virus, NOTCH signaling, immune suppression, brain tumor

DOI

10.1158/1078-0432.CCR-21-2347

PMID

35022322

PMCID

PMC8976724

PubMedCentral® Posted Date

10-1-2022

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes