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

Autor:	Otani Y; Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas., Yoo JY; Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas., Lewis CT; Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas., Chao S; Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas., Swanner J; Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas., Shimizu T; Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas., Kang JM; Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas., Murphy SA; Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas., Rivera-Caraballo K; Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas., Hong B; Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas., Glorioso JC; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Nakashima H; Harvey W. Cushing Neuro-Oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts., Lawler SE; Harvey W. Cushing Neuro-Oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts., Banasavadi-Siddegowda Y; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland., Heiss JD; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland., Yan Y; Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas., Pei G; Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, Texas., Caligiuri MA; City of Hope National Medical Center, Duarte, California., Zhao Z; Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, Texas.; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas., Chiocca EA; Harvey W. Cushing Neuro-Oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts., Yu J; City of Hope National Medical Center, Duarte, California., Kaur B; Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2022 Apr 01; Vol. 28 (7), pp. 1460-1473.
DOI:	10.1158/1078-0432.CCR-21-2347
Abstrakt:	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. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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