Cell stress proteins: novel immunotherapeutics.
Heat shock proteins (HSPs) play important roles in the immune system as carriers of tumour antigens and inflammatory agents. The HSPs are abundantly expressed stress proteins intrinsic to all cellular life, permitting proteins to carry out essential enzymic, signalling and structural functions within the tightly crowded milieu of the cell. To carry out these tasks, HSPs are equipped with a domain that binds unstructured sequences in polypeptides and a N-terminal ATPase domain that controls the opening and closing of the peptide-binding domain. HSPs can, using these domains, capture antigens processed by partial proteolysis in the cytoplasm of cancer cells. HSP/peptide complexes formed in the cytoplasm can then be secreted to take part in immune surveillance. Extracellular Hsp70 interacts with receptors on antigen presenting cells (APCs) either during episodes of cell death and lysis in vivo or during vaccination. A number of candidate receptors for Hsp70 on APCs have been proposed to take part in the antitumour immune function including the alpha2 macroglobulin receptor CD91, Toll-like receptors, the signalling receptor CD40 and a number of scavenger receptors. Finally, Hsp70 complexes are able to deliver antigens to MHC class I and II molecules on the APC cell surface and lead to the presentation of tumour antigens to T lymphocytes. HSP-antigen complexes have proven effective in the treatment of rodent tumours in preclinical studies and are now undergoing clinical trials for treatment of human cancer.
Calderwood
Stuart K
SK
Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Gong
Jianlin
J
Theriault
Jimmy R
JR
Mambula
Salamatu S
SS
Gray
Philip J
PJ
D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D005110:Extracellular Space / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology; D006360:Heat-Shock Proteins / Q000276:immunology* / Q000627:therapeutic use*; D006801:Humans; D008285:Major Histocompatibility Complex / Q000276:immunology; D009369:Neoplasms / Q000276:immunology
D019496:Cancer Vaccines; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins