Potent tumor-specific immunity induced by an in vivo heat shock protein-suicide gene-based tumor vaccine.
Tumor cells harbor a repertoire of unique, mutated antigens and shared self-antigens but generally are incapable of provoking an effective immune response, likely because of inadequate antigen presentation by professional antigen-presenting cells. Heat shock proteins (HSPs) play important roles in eliciting innate and adaptive immunity by chaperoning peptides for antigen presentation and providing endogenous danger signaling. Although effective in inducing tumor-specific immunity in mice and in some clinical trials, tumor-derived HSPs have many limitations like vaccines, such as the technical difficulty of ex vivo preparation of adequate quantities of HSPs from the resected tumors of individual patients. Here we have developed an in vivo HSP-suicide gene tumor vaccine by generating a recombinant replication-defective adenovirus (Ad-HT) that coexpresses HSP70 and a herpes simplex virus thymidine kinase suicide gene. The combination of HSP70 overexpression in situ and tumor killing by thymidine kinase/ganciclovir treatment, but neither strategy alone, provoked potent systemic antitumor activities after intratumor injection of Ad-HT. Tumor-specific CD4+ and CD8+ T-cell responses were induced by Ad-HT intratumor injection. CD11c+ dendritic cells (DCs) isolated from mice treated with Ad-HT were able to prime tumor-specific CTLs. Collectively, these results indicate that the combination of tumor killing by activation of a suicide gene to release tumor antigens and in situ HSP70 overexpression to enhance DC antigen presentation overcomes host immune tolerance to tumor antigens, leading to the induction of potent antitumor immunity. Our findings may have broad relevance to the use of the in vivo HSP/suicide gene tumor vaccine in therapy for human solid tumors.
Ren
Wenhong
W
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030, USA.
Strube
Randy
R
Zhang
Xiaoqing
X
Chen
Si-Yi
SY
Huang
Xue F
XF
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D015774:Ganciclovir / Q000493:pharmacokinetics / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D008213:Lymphocyte Activation / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
D019496:Cancer Vaccines; D018840:HSP70 Heat-Shock Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir