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Abstract
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.
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1 Department of Neurological Surgery, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
2 Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
3 Department of Molecular Genetics, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
4 Department of Neurological Surgery, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA; Surgical Neurology Branch, NINDS, National Institutes of Health, Bethesda, MD, USA
5 Department of Neurological Surgery, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
6 Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
7 Division of Biostatistics, Department of Information Sciences, City of Hope National Medical Center, Duarte, California, USA
8 Department of Pathology and Laboratory Medicine, The Brown Cancer Center, University of Louisville, Louisville, KY, USA
9 Hollings Cancer Center, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
10 Department of Hematology & Hematopoietic Cell Transplantation,, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA