title: Immune response is an important aspect of the antitumor effect produced by a CD40L-encoding oncolytic adenovirus.
abstract: Oncolytic adenovirus is an attractive platform for immunotherapy because virus replication is highly immunogenic and not subject to tolerance. Although oncolysis releases tumor epitopes and provides costimulatory danger signals, arming the virus with immunostimulatory molecules can further improve efficacy. CD40 ligand (CD40L, CD154) induces apoptosis of tumor cells and triggers several immune mechanisms, including a T-helper type 1 (T(H)1) response, which leads to activation of cytotoxic T cells and reduction of immunosuppression. In this study, we constructed a novel oncolytic adenovirus, Ad5/3-hTERT-E1A-hCD40L, which features a chimeric Ad5/3 capsid for enhanced tumor transduction, a human telomerase reverse transcriptase (hTERT) promoter for tumor selectivity, and human CD40L for increased efficacy. Ad5/3-hTERT-E1A-hCD40L significantly inhibited tumor growth in vivo via oncolytic and apoptotic effects, and (Ad5/3-hTERT-E1A-hCD40L)-mediated oncolysis resulted in enhanced calreticulin exposure and HMGB1 and ATP release, which were suggestive of immunogenicity. In two syngeneic mouse models, murine CD40L induced recruitment and activation of antigen-presenting cells, leading to increased interleukin-12 production in splenocytes. This effect was associated with induction of the T(H)1 cytokines IFN-γ, RANTES, and TNF-α. Tumors treated with Ad5/3-CMV-mCD40L also displayed an enhanced presence of macrophages and cytotoxic CD8(+) T cells but not B cells. Together, our findings show that adenoviruses coding for CD40L mediate multiple antitumor effects including oncolysis, apoptosis, induction of T-cell responses, and upregulation of T(H)1 cytokines.
authors.affiliation: Cancer Gene Therapy Group, Molecular Cancer Biology Program & Transplantation Laboratory & Haartman Institute & Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Iulia
authors.initials: I
authors.lastname: Diaconu
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerullo
authors.forename: Mari L M
authors.initials: ML
authors.lastname: Hirvinen
authors.forename: Sophie
authors.initials: S
authors.lastname: Escutenaire
authors.forename: Matteo
authors.initials: M
authors.lastname: Ugolini
authors.forename: Saila K
authors.initials: SK
authors.lastname: Pesonen
authors.forename: Simona
authors.initials: S
authors.lastname: Bramante
authors.forename: Suvi
authors.initials: S
authors.lastname: Parviainen
authors.forename: Anna
authors.initials: A
authors.lastname: Kanerva
authors.forename: Angelica S I
authors.initials: AS
authors.lastname: Loskog
authors.forename: Aristides G
authors.initials: AG
authors.lastname: Eliopoulos
authors.forename: Sari
authors.initials: S
authors.lastname: Pesonen
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D023201:CD40 Ligand / Q000235:genetics* / Q000276:immunology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D006801:Humans; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy* / Q000821:virology; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics* / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy / Q000821:virology; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D023201:CD40 Ligand