PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance

Luke Russell, Jessica Swanner, Alena Cristina Jaime-Ramirez, Yufeng Wang, Alex Sprague, Yeshavanth Banasavadi-Siddegowda, Ji Young Yoo, Gina M. Sizemore, Raleigh Kladney, Jianying Zhang, Norman L. Lehman, Michael C Ostrowski, Bangxing Hong, Michael Caligiuri, Jianhua Yu and Balveen Kaur ()
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Luke Russell: Ohio State University Comprehensive Cancer Center
Jessica Swanner: University of Texas Health Science Center at Houston
Alena Cristina Jaime-Ramirez: Ohio State University Comprehensive Cancer Center
Yufeng Wang: Ohio State University Comprehensive Cancer Center
Alex Sprague: Ohio State University Comprehensive Cancer Center
Yeshavanth Banasavadi-Siddegowda: Ohio State University Comprehensive Cancer Center
Ji Young Yoo: Ohio State University Comprehensive Cancer Center
Gina M. Sizemore: Ohio State University Comprehensive Cancer Center
Raleigh Kladney: Ohio State University Comprehensive Cancer Center
Jianying Zhang: City of Hope National Medical Center
Norman L. Lehman: University of Louisville
Michael C Ostrowski: Medical University of South Carolina
Bangxing Hong: University of Texas Health Science Center at Houston
Michael Caligiuri: City of Hope National Medical Center and Beckman Research Institute
Jianhua Yu: City of Hope National Medical Center and Beckman Research Institute
Balveen Kaur: University of Texas Health Science Center at Houston

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07344-1

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