Attraction and activation of dendritic cells at the site of tumor elicits potent antitumor immunity.
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.
Lapteva
Natalia
N
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.
Aldrich
Melissa
M
Rollins
Lisa
L
Ren
Wenhong
W
Goltsova
Tatiana
T
Chen
Si-Yi
SY
Huang
Xue F
XF
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
D017501:Adenovirus E1B Proteins; D019496:Cancer Vaccines; D023083:beta-Defensins