The Ohio State University / Xu B*
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.
Xu B1,2, Ma R2, Russell L2, Yoo JY3, Han J2, Cui H2,4, Yi P2,4, Zhang J5, Nakashima H6, Dai H2, Chiocca EA6, Kaur B3, Caligiuri MA7,8, Yu J1,2,7,8.
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.
Third Affiliated Hospital, Army Medical University, Chongqing, China.
Division of Biostatistics, Department of Information Sciences, City of Hope National Medical Center, Duarte, California, USA.
Department of Neurosurgery, Brigham and Women's Hospital and Harvey Cushing Neuro-oncology Laboratories, Harvard Medical School, Boston, Massachusetts, USA.
Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA.
Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA.