Secretory heat-shock protein as a dendritic cell-targeting molecule: a new strategy to enhance the potency of genetic vaccines

Abstract

DNA vaccines are an appealing strategy for inducing cytotoxic T-lymphocyte and antibody responses against tumor cells as well as infectious agents. Dendritic cells (DCs) play a critical role in inducing immune responses, but their potential is not fully utilized in the DNA vaccine setting since they take up only a minor fraction of the injected DNA. Here we describe a novel DNA vaccination strategy based on the targeting of a modified tumor-associated antigen, the human papilloma virus (HPV) type 16 E7 protein, to DCs by a heat-shock protein (HSP) to enhance antigen presentation and immune responses. Specifically, a chimerical HPV-E7 and HSP70 fusion gene preceded with a leader sequence was constructed. When mice were immunized with this construct, the DNA is taken up by various types of cells, which then produce and secrete an HPV-E7-HSP70 fusion protein that is targeted to DCs by the HSP70 portion of the chimerical molecule for antigen presentation. In studies to test the efficacy of this strategy, we demonstrated that DNA vaccination with this secretory HPV-E7-HSP70 construct strongly enhanced an antigen-specific CD8 þ T-cell response as well as a specific B-cell response in mice. Furthermore, this immunization approach not only protected mice against lethal challenge with an HPV E7-expressing tumor line (TC-1), but also showed a therapeutic effect against established tumors. The results of this study indicate that secretory HSPs can be broadly used to target tumorassociated antigens to DCs to enhance antigen-specific immune responses. Gene Therapy (2004) 11, 924-932.

‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity

“…Foreign tumor antigens fused to hsp70 DNA vaccine have been shown to induce enhanced antitumor immunity in murine tumor models. [10][11][12] Murine selfantigen TRP2 fusion to hsp70 DNA vaccine significantly induced protection antitumor immunity, but failed to generate therapeutic antitumor activity (Figure 1a and b). These observations suggest that although TRP2hsp70 DNA vaccine can enhance antitumor immunity, improvement to this model is needed.…”

“…Hsp70 has been fused to foreign antigens such as viral E7 or rat Her2/Neu to enhance the potency of DNA vaccines in murine tumor models. [10][11][12] Upon induction of maturation in vivo, DCs upregulate CCR7, a chemokine receptor that drives DCs to migrate to the lymphatics. 13 Once antigen-loaded DCs arrive at the local lymphatic organ, they process and present antigen to T cells.…”

Heat shock fusion protein induces both specific and nonspecific anti‐tumor immunity

“…A fusion protein between mycobacterial HSP65 and human papillomavirus (HPV) E7 protein was developed to treat human HPV-associated diseases [13] and is now in phase III clinical trials for treating HPV-associated anal dysplasia, genital warts, recurrent respiratory papillomatosis and cervical dysplasia. A DNA vaccine expressing a secreted form of HPV-E7-HSP70 (a fusion protein between mycobacterial HSP70 and the HPV E7 protein) was demonstrated to strongly stimulate antigen-specific CD8 + T cell responses and inhibit the growth of established tumors in mice [14]. A fusion protein between mycobacterial HSP65 and ovalbumin or influenza virus nucleoprotein was shown to elicit MHC class I-restricted, antigen-specific CTL [15].…”

L’apport des nouvelles technologies en vaccinologie

“…D'autres toxines bactériennes, comme la sous-unité B de la toxine de Shiga [29] ou l'antigène protecteur (PA) produit par Bacillus anthracis [30] sont également employés comme vecteurs d'antigènes. Des protéines de choc thermique, comme Hsp70 ou gp96, sont capables de se lier à divers récepteurs à la surface des CD, notamment au CD91 [31], et ont été employées dans plusieurs modèles expéri-mentaux pour vectoriser des antigènes [32].…”