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; Balveen Kaur

doi:10.1038/s41467-018-07344-1

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, Balveen Kaur

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

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.

Original language	English (US)
Article number	5006
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07344-1
State	Published - Dec 1 2018
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-018-07344-1

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Russell, L., Swanner, J., Jaime-Ramirez, A. C., Wang, Y., Sprague, A., Banasavadi-Siddegowda, Y., Yoo, J. Y., Sizemore, G. M., Kladney, R., Zhang, J., Lehman, N. L., Ostrowski, M. C., Hong, B., Caligiuri, M., Yu, J., & Kaur, B. (2018). PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance. Nature communications, 9(1), [5006]. https://doi.org/10.1038/s41467-018-07344-1

Russell, L, Swanner, J, Jaime-Ramirez, AC, Wang, Y, Sprague, A, Banasavadi-Siddegowda, Y, Yoo, JY, Sizemore, GM, Kladney, R, Zhang, J, Lehman, NL, Ostrowski, MC, Hong, B, Caligiuri, M, Yu, J & Kaur, B 2018, 'PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance', Nature communications, vol. 9, no. 1, 5006. https://doi.org/10.1038/s41467-018-07344-1

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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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AU - Banasavadi-Siddegowda, Yeshavanth

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AU - Sizemore, Gina M.

AU - Kladney, Raleigh

AU - Zhang, Jianying

AU - Lehman, Norman L.

AU - Ostrowski, Michael C.

AU - Hong, Bangxing

AU - Caligiuri, Michael

AU - Yu, Jianhua

AU - Kaur, Balveen

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N2 - 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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PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance

Abstract

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