title: Nectin-1 expression by squamous cell carcinoma is a predictor of herpes oncolytic sensitivity.
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.
authors.affiliation: Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Yu
authors.forename: Prasad S
authors.initials: PS
authors.lastname: Adusumilli
authors.forename: David P
authors.initials: DP
authors.lastname: Eisenberg
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Darr
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Ghossein
authors.forename: Sen
authors.initials: S
authors.lastname: Li
authors.forename: Shiquan
authors.initials: S
authors.lastname: Liu
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Singh
authors.forename: Jatin P
authors.initials: JP
authors.lastname: Shah
authors.forename: Yuman
authors.initials: Y
authors.lastname: Fong
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wong
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D006224:Cricetinae; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D015316:Genetic Therapy; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D000075983:Nectins; D050504:Oncolytic Viruses / Q000502:physiology*; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000378:metabolism; D016196:S Phase; D012680:Sensitivity and Specificity; D019076:Transgenes / Q000235:genetics; D014759:Viral Envelope Proteins / Q000378:metabolism; D053586:Virus Internalization; D023041:Xenograft Model Antitumor Assays
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules; C000619010:NECTIN1 protein, human; C000619015:Nectin1 protein, mouse; D000075983:Nectins; D053240:Receptors, Tumor Necrosis Factor, Member 14; D014759:Viral Envelope Proteins