TY - JOUR
T1 - NOTCH-Induced MDSC Recruitment after oHSV Virotherapy in CNS Cancer Models Modulates Antitumor Immunotherapy
AU - Otani, Yoshihiro
AU - Yoo, Ji Young
AU - Lewis, Cole T.
AU - Chao, Samantha
AU - Swanner, Jessica
AU - Shimizu, Toshihiko
AU - Kang, Jin Muk
AU - Murphy, Sara A.
AU - Rivera-Caraballo, Kimberly
AU - Hong, Bangxing
AU - Glorioso, Joseph C.
AU - Nakashima, Hiroshi
AU - Lawler, Sean E.
AU - Banasavadi-Siddegowda, Yeshavanth
AU - Heiss, John D.
AU - Yan, Yuanqing
AU - Pei, Guangsheng
AU - Caligiuri, Michael A.
AU - Zhao, Zhongming
AU - Antonio Chiocca, E.
AU - Yu, Jianhua
AU - Kaur, Balveen
N1 - Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-21-2347
DO - 10.1158/1078-0432.CCR-21-2347
M3 - Article
C2 - 35022322
AN - SCOPUS:85127593753
SN - 1078-0432
VL - 28
SP - 1460
EP - 1473
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -