PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance.,Nature Communications

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PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance.
Nature Communications ( IF 14.7 ) Pub Date : 2018-11-27 , DOI: 10.1038/s41467-018-07344-1
Luke Russell ₁ , Jessica Swanner ₂ , Alena Cristina Jaime-Ramirez ₁ , Yufeng Wang ₃ , Alex Sprague ₁ , Yeshavanth Banasavadi-Siddegowda _{1,

2,

4} , Ji Young Yoo _{1,

2} , Gina M Sizemore ₅ , Raleigh Kladney ₃ , Jianying Zhang ₆ , Norman L Lehman ₇ , Michael C Ostrowski ₈ , Bangxing Hong ₂ , Michael Caligiuri ₉ , Jianhua Yu ₉ , Balveen Kaur ₂

Affiliation

Department of Neurological Surgery, Ohio State University Comprehensive Cancer Center, Columbus, 43210, OH, USA.
Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, 77030, TX, USA.
Department of Molecular Genetics, Ohio State University Comprehensive Cancer Center, 43210, Columbus, OH, USA.
Surgical Neurology Branch, NINDS, National Institutes of Health, Bethesda, 20852, MD, USA.
Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center, Columbus, 43210, OH, USA.
Division of Biostatistics, Department of Information Sciences, City of Hope National Medical Center, Duarte, 91010, California, USA.
Department of Pathology and Laboratory Medicine, The Brown Cancer Center, University of Louisville, Louisville, 40202, KY, USA.
Hollings Cancer Center, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, 29425, SC, USA.
Department of Hematology & Hematopoietic Cell Transplantation,, City of Hope National Medical Center and Beckman Research Institute, Duarte, 91010, CA, USA.

Engineered oncolytic viruses are used clinically to destroy cancer cells and have the ability to boost anticancer immunity. Phosphatase and tensin homolog deleted on chromosome 10 loss is common across a broad range of malignancies, and is implicated in immune escape. The N-terminally extended isoform, phosphatase and tensin homolog deleted on chromosome 10 alpha (PTENα), regulates cellular functions including protein kinase B signaling and mitochondrial adenosine triphosphate production. Here we constructed HSV-P10, a replicating, PTENα expressing oncolytic herpesvirus, and demonstrate that it inhibits PI3K/AKT signaling, increases cellular adenosine triphosphate secretion, and reduces programmed death-ligand 1 expression in infected tumor cells, thus priming an adaptive immune response and overcoming tumor immune escape. A single dose of HSV-P10 resulted in long term survivors in mice bearing intracranial tumors, priming anticancer T-cell immunity leading to tumor rejection. This implicates HSV-P10 as an oncolytic and immune stimulating therapeutic for anticancer therapy.

中文翻译：

溶瘤疱疹病毒的 PTEN 表达指导 T 细胞介导的肿瘤清除。

工程化溶瘤病毒在临床上用于破坏癌细胞并具有增强抗癌免疫力的能力。10 号染色体缺失的磷酸酶和张力蛋白同源物在多种恶性肿瘤中很常见，并且与免疫逃逸有关。N 端延伸的异构体、磷酸酶和张力蛋白同系物在 10 号染色体 (PTENα) 上缺失，调节细胞功能，包括蛋白激酶 B 信号传导和线粒体三磷酸腺苷的产生。在这里，我们构建了 HSV-P10，一种复制的、表达 PTENα 的溶瘤疱疹病毒，并证明它抑制 PI3K/AKT 信号传导，增加细胞三磷酸腺苷分泌，并减少受感染肿瘤细胞中程序性死亡配体 1 的表达，从而引发适应性免疫反应并克服肿瘤免疫逃逸。单剂量的 HSV-P10 可使患有颅内肿瘤的小鼠长期存活，引发抗癌 T 细胞免疫，导致肿瘤排斥。这暗示 HSV-P10 作为抗癌治疗的溶瘤和免疫刺激疗法。

更新日期：2018-11-28

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