Incorporation of porcine adenovirus 4 fiber protein enhances infectivity of adenovirus vector on dendritic cells: implications for immune-mediated cancer therapy.
One strategy in cancer immunotherapy is to capitalize on the key immunoregulatory and antigen presenting capabilities of dendritic cells (DCs). This approach is dependent on efficient delivery of tumor specific antigens to DCs, which subsequently induce an anti-tumor T-cell mediated immune response. Human adenovirus serotype 5 (HAdV5) has been used in human studies for gene delivery, but has limited infection in DCs, which lack the proper receptors. Addition of the porcine fiber knob (PK) from porcine adenovirus type 4 to HAdV5 allows the virus to deliver genetic material via binding to glycosylated surface proteins and bypasses the coxsackie-and-adenovirus receptor required by wild-type HAdV5. In this study we explored the potential therapeutic applications of an adenovirus with PK-based tropism against cancers expressing mesothelin. Infectivity and gene transfer assays were used to compare Ad5-PK to wild-type HAdV5. Mouse models were used to demonstrate peptide specificity and T-cell responses. We show that the PK modification highly augmented infection of DCs, including the CD141+ DC subset, a key subset for activation of naïve CD8+ T-cells. We also show that Ad5-PK increases DC infectivity and tumor specific antigen expression. Finally, vaccination of mice with the Ad5-PK vector resulted in enhanced T-cell-mediated interferon gamma (IFN-γ) release in response to both mesothelin peptide and a tumor line expressing mesothelin. Ad5-PK is a promising tool for cancer immunotherapy as it improves infectivity, gene transfer, protein expression, and subsequent T-cell activation in DCs compared to wild-type HAdV5 viruses.
Washington University School of Medicine, Division of Gynecologic Oncology, St. Louis, United States of America.
Ivy
I
Wilkinson-Ryan
University of Chicago, Department of Neuro-oncology, Chicago, United States of America.
Julius
J
Kim
Washington University School of Medicine, Department of Pathology and Immunology, St. Louis, United States of America.
Sojung
S
Kim
Saint Jans Gathuis Hospital, Department of SJG Apotheek, Weert, The Netherlands.
Ferhat
F
Ak
Saint Louis University, Department of Biology, St. Louis, United States of America.
Lindzy
L
Dodson
Washington University School of Medicine, Department of Pathology and Immunology, St. Louis, United States of America.
Marco
M
Colonna
Washington University School of Medicine, Division of Gynecologic Oncology, St. Louis, United States of America.
Matthew
M
Powell
Washington University School of Medicine, Division of Gynecologic Oncology, St. Louis, United States of America.
David
D
Mutch
Washington University School of Medicine, Division of Surgery, St. Louis, United States of America.
Dirk
D
Spitzer
Washington University School of Medicine, Department of Pathology and Immunology, St. Louis, United States of America.
Ted
T
Hansen
Washington University School of Medicine, Division of Surgery, St. Louis, United States of America.
Simon P
SP
Goedegebuure
Washington University School of Medicine, Division of Cancer Biology, St. Louis, United States of America.
David
D
Curiel
Washington University School of Medicine, Division of Surgery, St. Louis, United States of America.
William
W
Hawkins
D000260:Adenoviruses, Human; D025662:Adenoviruses, Porcine / Q000235:genetics / Q000276:immunology; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology; D058851:GPI-Linked Proteins / Q000096:biosynthesis; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007167:Immunotherapy; D000090204:Mesothelin; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D013552:Swine; D014161:Transduction, Genetic
D036022:Capsid Proteins; D058851:GPI-Linked Proteins; C000715528:Msln protein, mouse; C018315:hexon capsid protein, Adenovirus; D000090204:Mesothelin