title: Attraction and activation of dendritic cells at the site of tumor elicits potent antitumor immunity.
abstract: Tumor cells harbor unique genetic mutations, which lead to the generation of immunologically foreign antigenic peptide repertoire with the potential to induce individual tumor-specific immune responses. Here, we developed an in situ tumor vaccine with the ability to elicit antitumor immunity. This vaccine comprised an E1B-deleted oncolytic adenovirus expressing beta-defensin-2 (Ad-BD2-E1A) for releasing tumor antigens, recruiting and activating plasmacytoid dendritic cells (pDCs). Intratumoral injections of Ad-BD2-E1A vaccine inhibited primary breast tumor growth and blocked naturally occurring metastasis in mice. Ad-BD2-E1A vaccination induced potent tumor-specific T-cell responses. Splenic and intratumoral DCs isolated from Ad-BD2-E1A-immunized mice were able to stimulate or promote the differentiation of naive T cells into tumor-specific cytotoxic T cells. We further found that the increased numbers of mature CD45RA(+)CD8alpha(+)CD40(+) pDCs infiltrated into Ad-BD2-E1A-treated tumors. The antitumor effect of Ad-BD2-E1A vaccination was abrogated in toll-like receptor 4 (TLR4) deficient mice, suggesting the critical role of TLR4 in the induction of antitumor immunity by Ad-BD2-E1A. The results of this study indicate that in situ vaccination with the oncolytic BD2-expressing adenovirus preferentially attracts pDCs and promotes their maturation, and thus elicits potent tumor-specific immunity. This vaccine represents an attractive therapeutic strategy for the induction of individualized antitumor immunity.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Lapteva
authors.forename: Melissa
authors.initials: M
authors.lastname: Aldrich
authors.forename: Lisa
authors.initials: L
authors.lastname: Rollins
authors.forename: Wenhong
authors.initials: W
authors.lastname: Ren
authors.forename: Tatiana
authors.initials: T
authors.lastname: Goltsova
authors.forename: Si-Yi
authors.initials: SY
authors.lastname: Chen
authors.forename: Xue F
authors.initials: XF
authors.lastname: Huang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D017501:Adenovirus E1B Proteins / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009369:Neoplasms / Q000276:immunology*; D050504:Oncolytic Viruses / Q000235:genetics; D023083:beta-Defensins / Q000235:genetics / Q000502:physiology
chemical_list: D017501:Adenovirus E1B Proteins; D019496:Cancer Vaccines; D023083:beta-Defensins