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

mia Rl male symbol antigens [17] associated with respective peptides derived from
these proteins. Furthermore, it was found in patients with hepatitis virus B-associated
hepatocellular carcinomas that a virus-specific peptide is associated with gp96
[18]. The peptide-binding property of gp96 has also been supported by a number of
biophysical and structural assays [19±23]. By protease mapping and cross-linking approaches,
the minimal peptide-binding site of gp96 was mapped to amino acid residues
624±630 in a highly conserved region [21]. In case of HSP70, the peptides can
be dissociated with ATP [24]. As expected, treatment of HSP70±peptide complex
with ATP leads to loss of immunogenicity [25]. Studies have also shown that HSP70
purified from human melanoma can activate T cells to recognize melanoma differentiation
antigens such as MART-1, gp100 and TRP-2 in a MHC-restricted manner
[26]. Moreover, HSP70 isolated from an allogeneic melanoma cell line can pulse
gp100-negative target cells for specific recognition by anti-gp100 CTL clones, indicating
that peptide binding by HSP70 is not restricted by MHC haplotypes. Structurally,
the peptide-binding pocket of DnaK, a prokaryotic HSP70, has been resolved [27].
12.1.3
HSPs are Adjuvants
HSPs can interact specifically with antigen-presenting cells (APCs), such as dendritic
cells (DCs), through receptor-dependent mechanism [28±32]. Such interaction
leads to DC activation evidenced by the production of pro-inflammatory cytokines,
and up-regulation of the surface expression of a number of co-stimulatory molecules
such as CD80 and CD86 [33±39]. Most of the attention has been focused on the role
of HSPs in productive immune responses. It should be kept in mind that HSPs
could also play roles in tolerance induction by inducing DCs to produce anti-inflammatory
cytokines. For example, it has been reported that small molecular weight
HSPs such as HSP27 could stimulate human monocytes to produce IL-10, which is
an anti-inflammatory cytokine [40].
12.1.4
HSPs are Involved in Cross-Priming
12.1 The Thesis
It has been commonly accepted that tumor antigens have to be cross-presented from
tumor cells to the MHC class I and class II molecules of APC for the priming of respective
CD8 + and CD4 + T cells due to lack of co-stimulatory molecules on tumor
cells. This is known as cross-presentation. The activation of naÒve T cells through
cross-presentation is defined as cross-priming [41, 42]. It has been observed that
HSP-chaperoned peptides can be presented to MHC class I through their common
receptor CD91 on the surface of APCs in vitro [43, 44]. Furthermore, immunization
with HSP-peptide complexes can clearly lead to the activation of CD8 + CTLs in vivo,
supporting the roles of HSPs in cross priming.
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