Gosei Ueda

Efficient Cross-Presentation by Heat Shock Protein 90-Peptide Complex-Loaded Dendritic Cells via an Endosomal Pathway

It is well-established that heat shock proteins (HSPs)-peptides complexes elicit antitumor responses in prophylactic and therapeutic immunization protocols. HSPs such as gp96 and Hsp70 have been demonstrated to undergo receptor-mediated uptake by APCs with subsequent representation of the HSP-associated peptides to MHC class I molecules on APCs, facilitating efficient cross-presentation. On the contrary, despite its abundant expression among HSPs in the cytosol, the role of Hsp90 for the cross-presentation remains unknown. We show here that exogenous Hsp90-peptide complexes can gain access to the MHC class I presentation pathway and cause cross-presentation by bone marrow-derived dendritic cells. Interestingly, this presentation is TAP independent, and followed chloroquine, leupeptin-sensitive, as well as cathepsin S-dependent endosomal pathways. In addition, we show that Hsp90-chaperoned precursor peptides are processed and transferred onto MHC class I molecules in the endosomal compartment. Furthermore, we demonstrate that immunization with Hsp90-peptide complexes induce Ag-specific CD8+ T cell responses and strong antitumor immunity in vivo. These findings have significant implications for the design of T cell-based cancer immunotherapy.

Tumor-derived heat shock protein 70-pulsed dendritic cells elicit tumor-specific cytotoxic T lymphocytes (CTLs) and tumor immunity

Vaccination with autologous tumor‐derived heat shock proteins (Hsp), such as Hsp70, Hsp90 and gp96, has been demonstrated to elicit specific immune responses against the tumor from which the Hsps were isolated. The effect of Hsp immunization is wholly dependent on the presence of functional antigen‐presenting cells (APCs) in the immunized host, and Hsp receptors on APCs have recently been identified. Here we show that bone marrow‐derived dendritic cells (DCs) are able to internalize HSP‐peptide complex and that peptides are re‐presented by DCs via the major histocompatibility complex (MHC) class I presentation pathway. In addition, immunization with tumor‐derived HSP‐pulsed DCs induces strong cytotoxic T cell (CTL) responses against multiple antigenic peptides in a transporter‐associated antigen processing (TAP)‐dependent manner. The results of the present study provide strong evidence of an efficient cross‐priming activity of Hsp70, which could be exploited in the development of new and more effective immunotherapeutic strategies for cancer patients. (Cancer Sci 2004; 95: 248–253)

T-Cell Receptor Variable γ Chain Gene Expression in the Interaction between Rat γδ-Type T Cells and Heat-Shock Protein 70-Like Molecule

We previously reported that rat T‐cell receptor (TCR) Vδ6 of T‐cell hybridomas was preferentially involved in recognition of the cell surface‐expressed 70 kDa rat heat‐shock cognate (hsc70, a constitutively expressed member of the hsp 70 family) protein‐like molecule (#067 molecule). In the present study, we analyzed usage of the TCR Vγ family of #067‐restricted T‐cell hybridomas. Our data indicated that most of these hybridomas expressed transcripts of TCR Vγ1 and/or Vγ2. However, some of the Vγ2 transcripts were out‐of‐frame, suggesting that the TCR Vγ1 family may be important for the recognition of #067‐defined molecules. TCR Vγ1 transcripts were detected in not only #067‐restricted T‐cell hybridomas, but #067‐non restricted ones as well. However, V‐J nucleotide sequences of #067‐restricted and #067‐non restricted T‐cell hybridomas suggested that #067‐restricted T‐cell hybridomas showed limited insertion of nucleotide stretch as compared with #067‐non restricted ones. In terms of amino acids, only one amino acid was added in #067‐restricted T‐cell hybridomas, whereas two or three amino acids were added in #067‐non restricted ones. These data suggest that the heterodimer of the TCR relatively short stretch form of Vγ1 molecule and TCR Vδ6 may participate in recognition of the #067 molecule.

Malignant Pheochromocytoma with Mandibular Metastasis

Abstract Malignant pheochromocytoma of the mandible is an extremely uncommon tumour. This report describes a 59-year-old woman with pheochromocytoma metastatic to the mandible. The patient was referred with a painless mandibular swelling on the right side. She had undergone dual tumour ablation for a pheochromocytoma of the adrenal medulla 7 years and 6 months previously, and for a pheochromocytoma metastatic lesion on the pelvis 2 years and 8 months previously. Radiographic examinations revealed a well-circumscribed radiolucent lesion of the mandibular ramus. A definitive diagnosis of malignant pheochromocytoma was made following a partial mandibulectomy. The patient died of disseminated intravascular coagulation and multiple bone metastases of pheochromocytoma about 10 years after the initial diagnosis of disease.