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

gp96 on tumor cells renders them regressive via a T lymphocyte-dependent mechanism.
This work not only demonstrated that surface expression of gp96 has a profound
influence on immunity, but also reinforced the notion that gp96 is an endogenous
DC activator.
Therefore, extracellular expression of HSPs might be an effective way to bridge innate
and adaptive immunity for cancer immunotherapy.
12.3
Conclusion and Perspectives
12.3 Conclusion and Perspectives
Although the immunological features of HSPs have been discovered in the context
of defining tumor antigens, it is now clear that HSPs play far-reaching roles in the
immune responses. The story of HSPs is somewhat analogous to that of MHC molecules.
The MHC was discovered as a major transplant barrier, but its ªnaturalº role
actually lies in antigen presentation. Different from HSPs, the function of MHC is
almost exclusively immunological with a few exceptions [89, 90], which permits the
creation of innovative animal models and sophisticated genetic studies. The study of
HSPs so far still relies on biochemistry, i.e. purification of HSPs and testing the immunological
properties of purified materials. This situation must change in order to
address the fundamental roles of HSPs in the physiological context. There are still
many unanswered questions.
(1) What are the roles of HSPs in antigen presentation? It has been proposed that various
HSPs constitute a relay line for peptide transfer from proteasome to MHC I
molecules [91]. However, this point has not been firmly proven even though
HSPs are peptide-binding proteins and there are generally no free-flowing peptides
in the cells [54]. Inhibition of peptide binding of HSP70 by 15-deoxyspergualin
inhibits antigen presentation to MHC class I [92], which is consistent
with the roles of HSP70 in antigen presentation; however, the finding could also
be explained by the roles of HSP70 in other cellular processes unrelated to peptide
binding. The major obstacles are lack of systems where each member of the
HSPs can be specifically manipulated and examined, and the fact that HSPs are
essential for life.
(2) Are HSPs involved in cross-presenting peptides to thymic T cells for positive or negative
selection? This is a logical question since if HSPs are indeed involved in the
priming of T cells, it should be expected that distal release of HSP±peptide complexes
(as a result of cell death or active secretion) in the neonatal period might
contribute to thymic T cell selection. This question has never been examined,
perhaps due to lack of a good experimental model.
(3) What are the contributions of HSPs to peripheral tolerance? The proponents for the
roles of HSPs in priming adaptive immunity have not examined this issue in
conditions where HSPs are released constantly, such as in patients with burns,
trauma, peripheral vascular diseases and infections. Similarly, the roles of HSPs
in immunopathology have not been carefully studied.
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