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

in Clinical cancer research : an official journal of the American Association for Cancer Research by 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

TLDR

  • The study investigated the impact of NOTCH blockade on virus-induced immunotherapy and found that pharmacologic blockade of NOTCH signaling enhanced antitumor immunity and improved therapeutic outcomes.

Abstract

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.

Overview

  • The study investigates the impact of NOTCH blockade on virus-induced immunotherapy, particularly in combination with oncolytic herpes simplex virus-1 (oHSV) infection of brain tumors.
  • The study used RNA sequencing (RNA-seq), TCGA data analysis, flow cytometry, Luminex- and ELISA-based assays, brain tumor animal models, and serum analysis to evaluate the effect of NOTCH signaling on virus-induced immunotherapy.
  • The primary objective of the study is to determine how NOTCH signaling affects the immunotherapy induced by oHSV infection of brain tumors and to explore therapeutic strategies to enhance antitumor immunity.

Comparative Analysis & Findings

  • The study found that NOTCH signaling significantly correlated with higher myeloid cell infiltration in TCGA data analysis and oHSV-treated experimental brain tumors in mice.
  • Immunofluorescence staining and RNA-seq revealed increased Jag1 (NOTCH ligand) expression in infiltrating myeloid cells upon oHSV infection, leading to NOTCH activation in the tumor microenvironment (TME).
  • Pharmacologic blockade of NOTCH signaling rescued the oHSV-induced immunosuppressive TME and activated a CD8-dependent antitumor memory response, resulting in therapeutic benefits, whereas NOTCH-induced immunosuppressive myeloid cell recruitment limited antitumor immunity.

Implications and Future Directions

  • The findings suggest that NOTCH inhibition in conjunction with oHSV therapy may enhance antitumor immunity, making it a potential therapeutic strategy for brain cancer treatment.
  • Future studies could focus on optimizing NOTCH inhibition protocols and exploring its combination with other immunotherapies to improve patient outcomes.
  • The study highlights the importance of understanding the immunosuppressive mechanisms in the tumor microenvironment and the potential therapeutic benefits of targeting specific signaling pathways, such as NOTCH.
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