Heat shock proteins in cancer immunotherapy

Transporter associated with antigen processing (TAP)-translocated peptides into the endoplasmic reticulum (ER) were demonstrated to bind to heat shock protein (HSP) gp96. In addition, TAP independently translocated peptides into the ER appears to bind to gp96. Also, tumor antigen peptide and its precursors were shown to be associated with cytosolic hsp90, hsp70 as well as ER luminal HSP gp96. These evidences are fully consistent with previous speculation that HSPs are associated with an entire repertoire of endogenous peptides destined to be major histocompatibility complex (MHC) class I ligands, which makes it possible to cross-prime across the MHC barrier. Vaccination of mice with HSPs covalently or non-covalently conjugated with synthetic peptides or protein in vitro have led to the generation of peptide specific cytotoxic T lymphocytes (CTLs) and conferred protective immunity against the pathogens or tumor growth in vivo. These observations have been repeatedly confirmed in a number of different model systems. Vaccination effect by HSPs for eradication of tumors which already existed has also been examined and shown to be effective especially in lung metastasis from local tumor. The possibility of cancer immunity elicited by peptides chaperoned by tumor-derived HSPs is now stimulating more than curiosity, and is becoming a solid rationale in terms of T cell priming in vivo; it also may provide a key to open a new avenue to the study of antigen processing/presentation.