Calcium depletion enhances nectin-1 expression and herpes oncolytic therapy of squamous cell carcinoma.
Attenuated, replication-competent, oncolytic herpes simplex virus type 1 (HSV-1) are effective at infecting and lysing many human malignancies in preclinical studies. Nectin-1 is a cell-surface receptor for HSV-1 envelope glycoprotein D (gD) that also forms a component of intercellular adherens junctions (AJs). We sought to determine if the disruption of AJs in squamous cell carcinoma (SCC) through calcium depletion could be utilized to increase nectin-1 exposure and enhance HSV therapy. NV1023 is a single copy gamma(1)34.5-deleted, lacZ-expressing, oncolytic HSV-1. Calcium depletion caused cell separation and increased nectin-1 expression for three SCC cell lines growing at confluence. NV1023 viral entry, soluble gD protein binding and NV1023 cytotoxicity were all significantly enhanced for these cell lines at low calcium conditions. The increase in NV1023 entry at low calcium conditions was abrogated by nectin-1 antibody blockade. Murine SCC flank tumors treated with ethylenediaminetetraacetic acid (EDTA) showed increased nectin-1 expression and increased susceptibility to NV1023 infection. Combined NV1023 and EDTA intratumoral injections demonstrated significantly enhanced tumor regression as compared to NV1023 alone. These findings establish, as proof-of-principle, that herpes viral receptor expression may be modulated on cancer cells to enhance oncolytic therapy. This strategy might have future application toward improving therapy with a variety of herpes vectors.
Yu
Z
Z
Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Li
S
S
Huang
Y-Y
YY
Fong
Y
Y
Wong
R J
RJ
D000818:Animals; D002118:Calcium / Q000172:deficiency*; D002294:Carcinoma, Squamous Cell / Q000628:therapy* / Q000821:virology; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000075983:Nectins; D050130:Oncolytic Virotherapy
D015815:Cell Adhesion Molecules; C000619010:NECTIN1 protein, human; C000619015:Nectin1 protein, mouse; D000075983:Nectins; D002118:Calcium