An oncolytic herpesvirus expressing E-cadherin improves survival in mouse models of glioblastoma

Bo Xu, Rui Ma, Luke Russell, Ji Young Yoo, Jianfeng Han, Hanwei Cui, Ping Yi, Jianying Zhang, Hiroshi Nakashima, Hongsheng Dai, E. Antonio Chiocca, Balveen Kaur, Michael A. Caligiuri, Jianhua Yu

Research output: Contribution to journalArticle

Abstract

The efficacy of oncolytic herpes simplex virus (oHSV) is limited by rapid viral clearance by innate immune effector cells and poor intratumoral viral spread. We combine two approaches to overcome these barriers: inhibition of natural killer (NK) cells and enhancement of intratumoral viral spread. We engineered an oHSV to express CDH1, encoding E-cadherin, an adherent molecule and a ligand for KLRG1, an inhibitory receptor expressed on NK cells. In vitro, infection with this engineered virus, named OV-CDH1, induced high surface E-cadherin expression on infected glioblastoma (GBM) cells, which typically lack endogenous E-cadherin. Ectopically expressed E-cadherin enhanced the spread of OV-CDH1 by facilitating cell-to-cell infection and viral entry and reduced viral clearance by selectively protecting OV-CDH1-infected cells from KLRG1+ NK cell killing. In vivo, OV-CDH1 treatment substantially prolonged the survival in GBM-bearing mouse models, primarily because of improved viral spread rather than inhibition of NK cell activity. Thus, virus-induced overexpression of E-cadherin may be a generalizable strategy for improving cancer virotherapy.

LanguageEnglish
Pages45-62
Number of pages18
JournalNature Biotechnology
Volume37
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Herpesviridae
Cadherins
Glioblastoma
Viruses
Natural Killer Cells
Oncolytic Viruses
Simplexvirus
Bearings (structural)
Virus Diseases
Ligands
Cells
Molecules
Infection
Neoplasms

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

Cite this

An oncolytic herpesvirus expressing E-cadherin improves survival in mouse models of glioblastoma. / Xu, Bo; Ma, Rui; Russell, Luke; Yoo, Ji Young; Han, Jianfeng; Cui, Hanwei; Yi, Ping; Zhang, Jianying; Nakashima, Hiroshi; Dai, Hongsheng; Chiocca, E. Antonio; Kaur, Balveen; Caligiuri, Michael A.; Yu, Jianhua.

In: Nature Biotechnology, Vol. 37, No. 1, 01.01.2019, p. 45-62.

Research output: Contribution to journalArticle

Xu, B, Ma, R, Russell, L, Yoo, JY, Han, J, Cui, H, Yi, P, Zhang, J, Nakashima, H, Dai, H, Chiocca, EA, Kaur, B, Caligiuri, MA & Yu, J 2019, 'An oncolytic herpesvirus expressing E-cadherin improves survival in mouse models of glioblastoma', Nature Biotechnology, vol. 37, no. 1, pp. 45-62. https://doi.org/10.1038/nbt.4302
Xu, Bo ; Ma, Rui ; Russell, Luke ; Yoo, Ji Young ; Han, Jianfeng ; Cui, Hanwei ; Yi, Ping ; Zhang, Jianying ; Nakashima, Hiroshi ; Dai, Hongsheng ; Chiocca, E. Antonio ; Kaur, Balveen ; Caligiuri, Michael A. ; Yu, Jianhua. / An oncolytic herpesvirus expressing E-cadherin improves survival in mouse models of glioblastoma. In: Nature Biotechnology. 2019 ; Vol. 37, No. 1. pp. 45-62.
@article{62884f98de574d63869d82df4d09d364,
title = "An oncolytic herpesvirus expressing E-cadherin improves survival in mouse models of glioblastoma",
abstract = "The efficacy of oncolytic herpes simplex virus (oHSV) is limited by rapid viral clearance by innate immune effector cells and poor intratumoral viral spread. We combine two approaches to overcome these barriers: inhibition of natural killer (NK) cells and enhancement of intratumoral viral spread. We engineered an oHSV to express CDH1, encoding E-cadherin, an adherent molecule and a ligand for KLRG1, an inhibitory receptor expressed on NK cells. In vitro, infection with this engineered virus, named OV-CDH1, induced high surface E-cadherin expression on infected glioblastoma (GBM) cells, which typically lack endogenous E-cadherin. Ectopically expressed E-cadherin enhanced the spread of OV-CDH1 by facilitating cell-to-cell infection and viral entry and reduced viral clearance by selectively protecting OV-CDH1-infected cells from KLRG1+ NK cell killing. In vivo, OV-CDH1 treatment substantially prolonged the survival in GBM-bearing mouse models, primarily because of improved viral spread rather than inhibition of NK cell activity. Thus, virus-induced overexpression of E-cadherin may be a generalizable strategy for improving cancer virotherapy.",
author = "Bo Xu and Rui Ma and Luke Russell and Yoo, {Ji Young} and Jianfeng Han and Hanwei Cui and Ping Yi and Jianying Zhang and Hiroshi Nakashima and Hongsheng Dai and Chiocca, {E. Antonio} and Balveen Kaur and Caligiuri, {Michael A.} and Jianhua Yu",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/nbt.4302",
language = "English",
volume = "37",
pages = "45--62",
journal = "Nature Biotechnology",
issn = "1087-0156",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - An oncolytic herpesvirus expressing E-cadherin improves survival in mouse models of glioblastoma

AU - Xu, Bo

AU - Ma, Rui

AU - Russell, Luke

AU - Yoo, Ji Young

AU - Han, Jianfeng

AU - Cui, Hanwei

AU - Yi, Ping

AU - Zhang, Jianying

AU - Nakashima, Hiroshi

AU - Dai, Hongsheng

AU - Chiocca, E. Antonio

AU - Kaur, Balveen

AU - Caligiuri, Michael A.

AU - Yu, Jianhua

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The efficacy of oncolytic herpes simplex virus (oHSV) is limited by rapid viral clearance by innate immune effector cells and poor intratumoral viral spread. We combine two approaches to overcome these barriers: inhibition of natural killer (NK) cells and enhancement of intratumoral viral spread. We engineered an oHSV to express CDH1, encoding E-cadherin, an adherent molecule and a ligand for KLRG1, an inhibitory receptor expressed on NK cells. In vitro, infection with this engineered virus, named OV-CDH1, induced high surface E-cadherin expression on infected glioblastoma (GBM) cells, which typically lack endogenous E-cadherin. Ectopically expressed E-cadherin enhanced the spread of OV-CDH1 by facilitating cell-to-cell infection and viral entry and reduced viral clearance by selectively protecting OV-CDH1-infected cells from KLRG1+ NK cell killing. In vivo, OV-CDH1 treatment substantially prolonged the survival in GBM-bearing mouse models, primarily because of improved viral spread rather than inhibition of NK cell activity. Thus, virus-induced overexpression of E-cadherin may be a generalizable strategy for improving cancer virotherapy.

AB - The efficacy of oncolytic herpes simplex virus (oHSV) is limited by rapid viral clearance by innate immune effector cells and poor intratumoral viral spread. We combine two approaches to overcome these barriers: inhibition of natural killer (NK) cells and enhancement of intratumoral viral spread. We engineered an oHSV to express CDH1, encoding E-cadherin, an adherent molecule and a ligand for KLRG1, an inhibitory receptor expressed on NK cells. In vitro, infection with this engineered virus, named OV-CDH1, induced high surface E-cadherin expression on infected glioblastoma (GBM) cells, which typically lack endogenous E-cadherin. Ectopically expressed E-cadherin enhanced the spread of OV-CDH1 by facilitating cell-to-cell infection and viral entry and reduced viral clearance by selectively protecting OV-CDH1-infected cells from KLRG1+ NK cell killing. In vivo, OV-CDH1 treatment substantially prolonged the survival in GBM-bearing mouse models, primarily because of improved viral spread rather than inhibition of NK cell activity. Thus, virus-induced overexpression of E-cadherin may be a generalizable strategy for improving cancer virotherapy.

UR - http://www.scopus.com/inward/record.url?scp=85059606021&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059606021&partnerID=8YFLogxK

U2 - 10.1038/nbt.4302

DO - 10.1038/nbt.4302

M3 - Article

VL - 37

SP - 45

EP - 62

JO - Nature Biotechnology

T2 - Nature Biotechnology

JF - Nature Biotechnology

SN - 1087-0156

IS - 1

ER -