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

12.2 Cancer Immunotherapy Strategies with HSPs
Tab. 12.2 T cell immunity against defined antigens induced by HSP±peptide complexes
Antigen HSP Reference
Intracellular bacteria (L.monocytogenes, MTB) gp96 104
Bovine herpes virus 1 gp96 105
Adenovirus type 5 E1B gp96 37
Ovalbumin CRT, gp96 16
HSP70, gp96 15
Mouse leukemia RL symbol 1 HSP90, gp96 and HSP70 17
Influenza virus nucleoprotein gp96 106
VSV nucleoprotein gp96 13
b-Galactosidase gp96 14
Minor Hantigens gp96 14
LCMV antigen HSP70 107
12.2.2.1 Non-covalent complex between HSP and antigenic peptides
The immunomodulating function of HSPs in the application of cancer therapy has
not been thoroughly explored. One reason is probably the observation that the optimal
immunity is elicited when antigen is physically complexed with HSPs [59]. Mixing
of the two alone without complexing is clearly suboptimal. Therefore, the effort
currently for using the adjuvanticity of HSPs is to complex HSPs with a known target
(antigen).
Gp96 can associate with peptides reproducibly in vitro by a simple heat-dependent refolding
assay. Such an interaction between gp96 and peptides has no apparent bias or
selectivity towards the sequence and length of the peptides [59]. Therefore, if a tumorassociated
peptide is defined, it can be easily complexed with gp96 and be used as a tumor
vaccine. The reconstituted gp96 peptide complex is efficient in priming CD8 + T
cells [59]. Using this strategy, it was demonstrated that immunization with gp96±VSV
peptide complex leads to rejection of thymoma that are made to express VSV.
To further prove the concept, gp96 and other HSPs have been complexed with various
infectious agents , and used successfully for generating pathogen-specific T cell
responses against lymphocytic choriomeningitis virus (LCMV), Listeria monocytogenes,
influenza A virus and SV-40 virus large Tantigen (Tab. 12.2).
HSP±peptide complex reconstituted in vitro retains other immunological functions
such as in cross-presentation. For example, pulsing of APCs with gp96 complexed
with a retroviral antigen, AH-1, can stimulate AH-1-specific CTLs to release IFN-g
[43]. This re-presentation pathway is dependent on the receptor CD91.
12.2.2.2 Covalent complex between HSP and antigenic peptides
Recombinant Mycobacterium tuberculosis (MTB) HSP70 fused covalently with a
model peptide has also been found to be highly immunogenic against the peptide
[60±62]. Using this system, it was found that the immunogenicity associated with
HSP70 fusion protein was dependent on a discrete 200-amino acid protein fragment
at the N-terminal ATP-binding domain [63]. The implication for the function of
HSP70 is unclear, since the fusion protein may have adopted a different conforma-
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