Heat‐shock proteins as dendritic cell‐targeting vaccines – getting warmer

Abstract

SummaryHeat-shock proteins (hsp) provide a natural link between innate and adaptive immune responses by combining the ideal properties of antigen carriage (chaperoning), targeting and activation of antigen-presenting cells (APC), including dendritic cells (DC). Targeting is achieved through binding of hsp to distinct cell surface receptors and is followed by antigen internalization, processing and presentation. An improved understanding of the interaction of hsp with DC has driven the development of numerous hsp-containing vaccines, designed to deliver antigens directly to DC. Studies in mice have shown that for cancers, such vaccines generate impressive immune responses and protection from tumour challenge. However, translation to human use, as for many experimental immunotherapies, has been slow partly because of the need to perform trials in patients with advanced cancers, where demonstration of efficacy is challenging. Recently, the properties of hsp have been used for development of prophylactic vaccines against infectious diseases including tuberculosis and meningitis. These hsp-based vaccines, in the form of pathogenderived hsp-antigen complexes, or recombinant hsp combined with selected antigens in vitro, offer an innovative approach against challenging diseases where broad antigen coverage is critical.

Influence of Escherichia coli chaperone DnaK on protein immunogenicity

“…Given the documented effect of HSPs on adjuvanticity,14, 15 we hypothesized that these contaminants could be responsible for the enhanced IgG responses for Fraction A versus Fraction M aggregates presented in Fig. 2.…”

“…Furthermore, the principal function of HSPs is to mediate the correct folding of proteins inside the cell and therefore, by nature, they bind to partially unfolded proteins 20. We also noted that the ability of HSPs to enhance the immunogenicity of a co‐administered antigen is well‐documented, with the successful use of HSPs in vaccine development 15. We accordingly selected the E. coli HSP DnaK, and studied this individually as a candidate HCP impurity.…”

“…Heat‐shock proteins (HSPs) are molecular chaperones, and bacterial HSPs have been shown to augment adaptive immune responses 14. In vaccine development HSPs are now being exploited to improve efficacy 15. For example, a novel vaccine strategy for Neisseria meningitidis uses a bacterial HSP in a protein antigen–HSP complex that enhances antigen immunogenicity 16.…”

Trial Watch: Peptide-based anticancer vaccines

“…Of these studies, 13 rely on one or more TAA-derived short peptides injected as such (NCT01949688; NCT01949701; NCT01950156; NCT01961115; NCT01970358; NCT01989559; NCT01989572; NCT02019524; NCT02077114; NCT02126579; NCT02134925; NCT02149225; NCT02193347), 2 on TAA-derived short peptides encapsulated within liposomes (NCT01978964; NCT02065973), 1 on an SLP (NCT02128126), 1 on a CMP (NCT02229084), 1 on a full length, recombinant TAA (NCT02015416), and one on purified TAAs complexed with heat shock protein 90kDa b (Grp94), member 1 (HSP90B1, best known as gp96) [190][191][192][193][194] (NCT02122822) ( Table 1).…”

The progress of immunotherapy for glioblastoma

“…While the application of tumor-derived heat shock proteins (HSPs) as tumor antigen carrier can make use of DCs' antigen-presenting function without requiring the culture of DCs in vitro. 16 Belonging to a protein family whose main physiological function is to promote the mechanism of peptide folding by interacting with polypeptides, HSPs express at a higher level in case of fever, infection, hypoxia, cancer and other conditions. In addition, HSPs can be combined with the DCs and transfer the bound polypeptide antigens into them, thus activating CD4C and CD8C T cell response in tumor immunotherapy.…”