1. ¹Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
2. ²Department of Otolaryngology, Beijing Tongren Hospital, Capital University of Medical Sciences, Beijing, China
3. ³Hepatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
4. ⁴Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

Correspondence: Richard J Wong, Head and Neck Service, C-1069, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. E-mail: wongr@mskcc.org

Received 13 April 2006; Accepted 6 August 2006.

Abstract

Oncolytic viruses based on herpes simplex virus type 1 (HSV-1) are able to infect and lyse a variety of malignant cell lines. However, there is variability in the degree of tumor susceptibility, and the cancer cell determinants of HSV sensitivity are poorly defined. Nectin-1 is a cell surface adhesion molecule that functions as a cellular receptor to HSV envelope glycoprotein D (gD). We assessed tumor nectin-1 expression as a predictor of oncolytic HSV sensitivity. A panel of human squamous carcinoma cell lines was evaluated for viral entry, replication, and cytotoxicity to an attenuated, replication-competent, oncolytic HSV (NV1023). Potential tumor determinants of HSV sensitivity were assessed, including nectin-1, herpes viral entry mediator, total gD receptor expression, S-phase fraction, and doubling time. Significant correlations between nectin-1 expression measured by quantitative fluorescence-activated cell sorting and viral sensitivity measures were identified using Pearson's coefficients. Cancer cell nectin-1 receptor blockade and nectin-1 transfection led to inhibition and enhancement of NV1023 viral entry, respectively. Cell lines with varying nectin-1 expression showed corresponding sensitivity to NV1023 therapy in vivo. Immunohistochemistry for nectin-1 was inversely related to E-cadherin staining, suggesting increased herpes sensitivity of E-cadherin-deficient tumors. These results suggest that nectin-1 may be used as a marker to predict the sensitivity of a tumor to herpes oncolytic therapy.