한빛사논문
- 조회289
Min Hye Noh1*, Jin Muk Kang1,10*, Alexandra A. Miller1,2, Grace Nguyen1, Minxin Huang1, Ji Seon Shim1, Alberto J Bueso-Perez1, Sara A. Murphy2,3, Kimberly A. Rivera-Caraballo2,3, Yoshihiro Otani1,4, Eunju Kim5,11, Seung-Hee Yoo5, Yuanqing Yan1,6, Yeshavanth Banasavadi-Siddegowda7, Hiroshi Nakashima8, E. Antonio Chiocca8, Balveen Kaur3, Zhongming Zhao9, Tae Jin Lee1,2#, and Ji Young Yoo1,2#
1Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
2The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Science, Houston, TX 77025, USA.
3Georgia Cancer Center and Department of Pathology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, CN-3311, Augusta, GA 30912, USA.
4Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
5Department of Biochemistry, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
6Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
7Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20852, USA.
8Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
9Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
10Department of Pediatric Hematology & Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA.
11Department of Food and Nutriton, Kongju National University, Yesan, Chungnam, 32439, South Korea.
*These authors are equally contributed.
#Address correspondence and reprint request to: Dr. Ji Young Yoo, Dr. Tae Jin Lee
Abstract
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=0.0020) (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.
Conclusion: 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.
논문정보
- Research article
- 2024년 06월 (BRIC 등록일 2024-06-21)
- 국외 연구진
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