Abstract
Heat shock proteins (HSP) have been revealed to interact with antigen-presenting cells and have potent adjuvant capability to induce antigen-specific CD8+ CTL and Th1 responses. Our previous work shows how Hsp70-like protein 1 (Hsp70L1), as a new member of the Hsp70 subfamily, acts as potent Th1 adjuvant. Here, we report the efficient induction of tumor antigen-specific immune response by dendritic cells pulsed with recombinant fusion protein of Hsp70L1 and CEA(576-669) fragment of the carcinoembryonic antigen (CEA) containing CAP-1 (a HLA-A2-restricted CTL epitope). Fusion protein CEA(576-669)-Hsp70L1 can promote dendritic cell maturation and activate dendritic cells to produce cytokines, such as interleukin-12, interleukin-1beta, and tumor necrosis factor-alpha, and chemokines, such as macrophage inflammatory protein-1alpha, macrophage inflammatory protein-1beta, and regulated on activation, normal T expressed and secreted, indicating the adjuvant ability of Hsp70L1 in the fusion protein. CEA-specific HLA-A2.1-restricted CD8+ CTLs either from patients with CEA+/HLA-A2.1+ colon carcinoma or from splenocytes of immunized HLA-A2.1/Kb transgenic mice can be generated more efficiently after stimulations or immunizations with dendritic cells pulsed by CEA(576-669)-Hsp70L1 than with dendritic cells pulsed by CEA(576-669) alone, resulting in secreting more Th1 cytokine IFN-gamma and killing target cells more potently in an antigen-specific and HLA-A2.1-restricted manner. Adoptive transfer of splenocytes from transgenic mice immunized with CEA(576-669)-Hsp70L1-pulsed dendritic cells can inhibit tumor growth and prolong survival in nude mice bearing CEA+/HLA-A2.1+ human colon carcinoma more markedly. Therefore, Hsp70L1 has potent adjuvant effect in form of fusion protein, indicating that Hsp70L1 may be widely used as Th1 adjuvant to prepare antigenic fusion protein for the therapeutics of cancer or infectious diseases.
Highlights
Heat shock proteins (HSP) are reported to act as an effective adjuvant to enhance the induction of antigen peptide-specific cellular immunity [1, 2]
We showed that the efficiency of presentation of antigenic epitopes in CEA576-669 was enhanced by its fusion with Hsp70-like protein 1 (Hsp70L1) through unique adjuvant effects on dendritic cells and leading to more significant induction of epitope-specific CD8+ CTLs that recognized and killed carcinoembryonic antigen (CEA)-expressing tumor cells
We observed an increase in IL-12p40, tumor necrosis factor-a (TNF-a), and IL-1h secretions by CEA576-669-Hsp70L1stimulated or Hsp70L1-stimulated dendritic cells but not CEA576-669stimulated dendritic cells (P < 0.05; Fig. 1B)
Summary
Heat shock proteins (HSP) are reported to act as an effective adjuvant to enhance the induction of antigen peptide-specific cellular immunity [1, 2]. HSP-peptide complexes can be taken quite efficiently in a receptor-mediated manner by antigen-. HSP-peptide complexes isolated from intact tumor cells or virus-infected cells or reconstituted by covalent cross-link or fusion-protein strategies are all capable of eliciting potent CD8+ CTL responses to the antigenic peptides bound to the HSP [1, 2, 8,9,10,11]. Vaccination approaches have even been evaluated in phase III clinical trials for the treatment of human papillomavirus–related carcinoma [12]
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