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Recent Progress and Perspective of Human Cancer Peptide Immunotherapy by Using Heat Shock Proteins |
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Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, JAPAN |
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| We have studied human tumor antigens applicable for a wide variety of tumors, and determined immunogenic peptide epitopes from these tumor antigen molecules presented particularly by HLA-A24. Our study indicated that peptides (survivin 2B) derived from survivin, an inhibitor of apoptosis proteins (IAP), are immunogenic in more than 50% of cancer patients with a wide variety of tumors. These vaccine candidates are now under clinical trials, and with careful immunological monitoring, we would be able to know finally if these vaccines can work clinically. To establish a potent clinical protocol, the immunological tumor escape mechanism should be more drastically examined in human materials. We have recently succeeded in establishing anti-HLA-A, B, and C alleles-specific monoclonal antibody EMR8-5 which can be used in routine paraffin-embedded sections. Unexpectedly enough, our data indicated that high percentage of human cancers lost HLA-class I molecules in primary cancer tissues. Particularly, more than 80% of breast and prostate cancers lost HLA-class I. Metastatic breast cancers indicated almost complete loss of HLA-class I. I will discuss possibilities for resolution of this old but yet new important problem. Meanwhile, recent evidences have been accumulating for an important role of the heat shock proteins (HSPs) as so called danger signals in initiating innate immunity as well as acquired immunity. The precise immunological basis for this phenomenon remains to be elucidated. T-cell immunity could be achieved after vaccination with tumor cells with MHC mismatching, which could not present antigen to T cells directly. This phenomenon is known as cross priming, and it may be mediated by Hsp-peptide complexes which are released from tumor cells. We show that exogenous Hsp90-peptide complexes can gain access to MHC class I presentation pathway and cause cross priming by bone marrow derived dendritic cells. Interestingly, this presentation is TAP-independent and follows endocytic pathways. We also show Hsp90-peptide complexes as a potential tumor vaccine by using HLA-A24 transgenic mouse model. | ||
| Key words: Cytotoxic T lymphocytes, HLA, Cancer vaccine, Heat shock proteins, Cross-presentation | ||
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