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

256 12 Principles and Strategies Employing Heat Shock Proteins for Immunotherapy of Cancers
12.1.5
Other Roles
Additionally, HSPs have been found to be expressed on the cell surface, and in various
scenarios HSPs can serve as direct targets for gd T cells [45, 46], NK cells [47]
and CD4 ± CD8 ± T cells [48]. These intriguing findings illustrate the plasticity of HSPs
in immune responses, and certainly prompt more research into the structural and
mechanistic basis of their actions.
12.2
Cancer Immunotherapy Strategies with HSPs
The emerging immunological principles of HSPs have stimulated interests in the
development of HSPs as tumor vaccines. There are generally three strategies
(Fig. 12.2). First, purified autologous tumor-derived HSPs can be used as tumor vaccines
based on the fact that tumor-derived HSPs chaperone antigenic peptides and
prime adaptive immunity. Second, defined tumor antigens can be fused either covalently
or non-covalently to HSPs and used as a T cell vaccine due to the adjuvanticity
of HSPs. Third, manipulation of the site and level of HSP expression in the tumor
cells have been shown to stimulate tumor-specific immunity.
12.2.1
Strategy 1: Autologous HSPs as Tumor-Specific Vaccines
Extensive transplantation experiments with syngeneic tumors in the 1950s [49±53]
have demonstrated that tumor rejection antigens responsible for tumor-protective
immunity are private, or individually distinct. Thus tumor A cannot immunize
against tumor B and vice versa even though tumor A and B are derived from the
same histological types, induced by the same carcinogen or even developed in the
same host. This phenomenon revealed one fundamentally important obstacle of cancer
immunotherapy, i.e. immunotherapy of cancer has to be individualized. Shared
antigens that are conserved among cancers such as differentiation antigen and genes
involved in tumorigenesis (oncogene or tumor suppressor genes) are probably not
effective tumor rejection antigens.
This argument suggests that antigenic composition is different among tumors, and
predicts that the effective cancer vaccine has to be derived from autologous tumors.
Since HSPs can bind to peptides with broad specificity and there are no free-flowing
peptides inside the cells [54], it has been suggested that peptides bound to HSPs represent
a total cellular peptide pool [3, 55], which forms a basis for tumor vaccines
with autologous tumor-derived HSPs.
The phenomenology of tumor-specific protection by immunization with tumor-specific
HSPs in experimental animals is widespread [3, 9]. In addition, purified tumorderived
HSP±peptide complexes are potent vaccines for pre-established cancers such
as lung, melanoma, lymphoma, fibrosarcoma, adenocarcinoma of the colon, sar-