Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

254 12 Principles and Strategies Employing Heat Shock Proteins for Immunotherapy of Cancers
Fig. 12.1 Immunological principles of HSPs. At
least four immunological principles of HSP in tumor
immunity have been described. (A) HSPs
are rarely tumor-specific antigens due to altered
structure or mutations. (B) HSPs are carriers for
12.1.1
HSPs per se are rarely Tumor Antigens
HSPs are well-conserved molecules in evolution with limited polymorphism.
Although HSP expression can be down-regulated and up-regulated in relation to
cancers, no cancer specific ªhotspotsº of mutations have been described. In only one
published example, mutation of HSP70 occurred in renal cell carcinoma and the
mutated HSP70 molecule served as the target for tumor-specific cytotoxic T lymphocytes
(CTLs) [10]. This is an exception rather than a rule.
12.1.2
HSPs are Molecular Chaperones for Antigenic Peptides
intracellular antigenic peptides. (C) HSPs activate
DCs by binding directly to HSP receptor(s)
on DCs. (D) HSP chaperoned peptides can be
cross-presented to MHC molecules on DCs for
cross-priming of T cells.
This concept was proposed to explain the dilemma that immunization with structurally
normal HSPs purified from tumor cells, but not from normal cells, confers tumor
specific immunity [11, 12]. The principle has since been confirmed structurally
and immunologically in the HSP70 and HSP90 family. The resolution of the HSP±
peptide complex is largely achieved by studying if HSPs can associate with immunologically
defined peptides [3]. For example, gp96 purified from vesicular stomatitis
virus (VSV)-infected cells, but not uninfected cells, was associated with an 8mer
VSV-derived peptide as revealed by both structural and immunological assays [13].
Similarly, it was shown that highly purified gp96 from cells expressing b-galactosidase,
minor histocompatibility antigens [14], ovalbumin [15, 16] and murine leuke-