Immune response and escape in human cancers

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The investigation of human tumor immunotherapy has remarkably advanced in the past decade. In our laboratory, human tumor antigens and their HLA-A24-restricted immunogenic peptide epitopes were determined to develop therapeutic and prophylactic human cancer vaccines. Among these peptides, survivin 2B peptide derived from survivin, an inhibitor of apoptosis protein (IAP), is immunogenic in more than 50 % of cancer patients with a wide variety of tumors, including colon, pancreas, lung, breast, urinary bladder and oral cancers. It is now under clinical and with careful immunological monitoring we will finally be able to know if these vaccines can work clinically.To develop a potent clinical therapeutic protocol, the immunological tumor escape mechanism should be more thoroughly examined in human tumor materials. To this end, anti-HLA-A, B, and C allele-specific monoclonal antibody EMR8-5, which can be used in routine paraffin-embedded sections, was successfully established. Unexpectedly, our data indicated that a high percentage of human cancers, particularly breast and prostate cancers, lost HLA-class I molecules in their primary cancer tissues. We will discuss possibilities for resolution of this important old but yet new problem.Although recent evidence has been accumulating for an important role of the heat shock proteins (HSPs) as so-called danger signals in initiating innate immunity and consequently activating acquired immunity, the precise immunological basis for this phenomenon remains to be elucidated. Our study indicated that certain HSP-chaperoned immunogenic peptides, particularly HSP90, could efficiently enter the cross-priming pathway in dendritic cells. Interestingly, this cross-priming was TAP-independent and followed endocytic pathways. We also showed that HSP90-chaperoned peptide complexes could work as a potential tumor therapeutic vaccine in the HLA-A24 transgenic mouse model.