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.

Details

Title
PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance
Author
Russell, Luke 1 ; Swanner, Jessica 2 ; Jaime-Ramirez, Alena Cristina 1 ; Wang, Yufeng 3 ; Sprague, Alex 1 ; Banasavadi-Siddegowda, Yeshavanth 4 ; Ji Young Yoo 5   VIAFID ORCID Logo  ; Sizemore, Gina M 6 ; Kladney, Raleigh 3 ; Zhang, Jianying 7 ; Lehman, Norman L 8 ; Ostrowski, Michael C 9 ; Hong, Bangxing 2 ; Caligiuri, Michael 10 ; Yu, Jianhua 10   VIAFID ORCID Logo  ; Kaur, Balveen 2 

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 
Pages
1-16
Publication year
2018
Publication date
Nov 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-07344-1
ProQuest document ID
2138606410
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.