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 - Funding Information:
J. Swanner reports grants from American Cancer Society and National Institute of Neurological Disorders and Stroke during the conduct of the study. H. Nakashima reports grants from NIH outside the submitted work. Z. Zhao reports grants from Cancer Prevention and Research Institute of Texas during the conduct of the study.
Funding Information:
We thank Li Xin (University of Washington) and Xiang Zhang (Baylor College of Medicine) for providing the DN-MAML plasmid. We thank the support from the Cancer Prevention and Research Institute of Texas (CPRIT RP180734 to Z. Zhao and RP210045 to Z. Zhao and B. Kaur), NIH P01CA163205 (to B. Kaur, E.A. Chiocca, M.A. Caliguri, and J.C. Glorioso), and American Cancer Society RSG-19–185–01-MPC (to J. Yu).
Funding Information:
We thank Li Xin (University of Washington) and Xiang Zhang (Baylor College of Medicine) for providing the DN-MAML plasmid. We thank the support from the Cancer Prevention and Research Institute of Texas (CPRIT RP180734 to Z. Zhao and RP210045 to Z. Zhao and B. Kaur), NIH P01CA163205 (to B. Kaur, E.A. Chiocca, M.A. Caliguri, and J.C. Glorioso), and American Cancer Society RSG-19?185?01MPC (to J. Yu).
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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UR - http://www.scopus.com/inward/citedby.url?scp=85127593753&partnerID=8YFLogxK
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 -
