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

• Published in: Clinical cancer research Vol. 28; no. 7; pp. 1460 - 1473
• Main Authors: Otani, Yoshihiro, Yoo, Ji Young, Lewis, Cole T., Chao, Samantha, Swanner, Jessica, Shimizu, Toshihiko, Kang, Jin Muk, Murphy, Sara A., Rivera-Caraballo, Kimberly, Hong, Bangxing, Glorioso, Joseph C., Nakashima, Hiroshi, Lawler, Sean E., Banasavadi-Siddegowda, Yeshavanth, Heiss, John D., Yan, Yuanqing, Pei, Guangsheng, Caligiuri, Michael A., Zhao, Zhongming, Chiocca, E. Antonio, Yu, Jianhua, Kaur, Balveen
• Format: Journal Article
• Language: English
• Published: United States 01.04.2022
• Subjects: Animals; Cell Line, Tumor; Glioblastoma - pathology; Humans; Immunotherapy; Mice; Myeloid-Derived Suppressor Cells - metabolism; Neoplasm Recurrence, Local - therapy; Oncolytic Virotherapy - methods; Oncolytic Viruses - genetics; Simplexvirus; Tumor Microenvironment; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-21-2347

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. 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. 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. NOTCH-induced immunosuppressive myeloid cell recruitment limited antitumor immunity. Translationally, these findings support the use of NOTCH inhibition in conjunction with oHSV therapy.