Targeting IGF2 to reprogram the tumor microenvironment for enhanced viro-immunotherapy.

Autor:	Noh MH; Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Kang JM; Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA.; Department of Pediatric Hematology & Oncology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA., Miller AA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Science, Houston, Texas, USA.; Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Nguyen G; Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Huang M; Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Shim JS; Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Bueso-Perez AJ; Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Murphy SA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Science, Houston, Texas, USA.; Georgia Cancer Center and Department of Pathology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA., Rivera-Caraballo KA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Science, Houston, Texas, USA.; Georgia Cancer Center and Department of Pathology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA., Otani Y; Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.; Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Kim E; Department of Food and Nutriton, Kongju National University, Yesan, Chungnam, South Korea.; Department of Biochemistry, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Yoo SH; Department of Biochemistry, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Yan Y; Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.; Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Banasavadi-Siddegowda Y; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA., Nakashima H; Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Maryland, USA., Chiocca EA; Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Maryland, USA., Kaur B; Georgia Cancer Center and Department of Pathology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA., Zhao Z; Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Lee TJ; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Science, Houston, Texas, USA.; Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Yoo JY; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Science, Houston, Texas, USA.; Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2024 Sep 05; Vol. 26 (9), pp. 1602-1616.
DOI:	10.1093/neuonc/noae105
Abstrakt:	Background: The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME). Methods: RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance. Results: Transcriptome analysis identified IGF2 as one of the top-secreted proteins following oHSV treatment. Moreover, IGF2 expression was significantly upregulated in 10 out of 14 recurrent GBM patients after treatment with oHSV, rQNestin34.5v.2 (71.4%; P = .0020) (ClinicalTrials.gov, NCT03152318). Depletion of IGF2 substantially enhanced oHSV-mediated tumor cell killing in vitro and improved survival of mice bearing BCBM tumors in vivo. To mitigate the oHSV-induced IGF2 in the TME, we constructed a novel oHSV, oHSV-D11mt, secreting a modified IGF2R domain 11 (IGF2RD11mt) that acts as IGF2 decoy receptor. Selective blocking of IGF2 by IGF2RD11mt significantly increased cytotoxicity, reduced oHSV-induced neutrophils/PMN-MDSCs infiltration, and reduced secretion of immune suppressive/proangiogenic cytokines, while increased CD8 + cytotoxic T lymphocytes (CTLs) infiltration, leading to enhanced survival in GBM or BCBM tumor-bearing mice. Conclusions: This is the first study reporting that oHSV-induced secreted IGF2 exerts a critical role in resistance to oHSV therapy, which can be overcome by oHSV-D11mt as a promising therapeutic advance for enhanced viro-immunotherapy. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
Databáze:	MEDLINE
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