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• 2013年

  　

  　

  札幌医科大学   医学部   助教

  助教

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• ライフサイエンス   整形外科学  

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• 札幌医科大学   医学部   助教  

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• 骨肉腫抗原

• 軟部腫瘍学

• ファージディスプレイライブラリ

• 骨

• HLA/ペプチド複合体

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• Heat shock protein 90 targets a chaperoned peptide to the static early endosome for efficient cross-presentation by human dendritic cells

  Tsutomu Tanaka, Koichi Okuya, Goro Kutomi, Akari Takaya, Toshimitsu Kajiwara, Takayuki Kanaseki, Tomohide Tsukahara, Yoshihiko Hirohashi, Toshihiko Torigoe, Koichi Hirata, Yoshiharu Okamoto, Noriyuki Sato, Yasuaki Tamura

  CANCER SCIENCE ( WILEY-BLACKWELL )  106 ( 1 ) 18 - 24  2015年01月  [査読有り]

  　概要を見る

  The presentation of an exogenous antigen in a major histocompatibility complex class-I- restricted fashion to CD8(+) T cells is called cross-presentation. Heat shock proteins (HSPs) such as Hsp70, gp96, and Hsp90 have been shown to elicit efficient CTL responses by cross-presentation through an as-yet entirely unknown mechanism. Hsp90 is the most abundant cytosolic HSP and is known to act as a molecular chaperone. We have shown that a tumor antigen peptide complexed with Hsp90 could be cross-presented by dendritic cells (DCs) through an endosomal pathway in a murine system. However, it has not been determined whether human DCs also cross-present an Hsp90-peptide complex and induce peptide-specific CTLs. In this study, we found that an Hsp90-cancer antigen peptide complex was efficiently cross-presented by human monocyte-derived DCs and induced peptide-specific CTLs. Furthermore, we observed that the internalized Hsp90-peptide complex was strictly sorted to the Rab5(+), EEA1(+) static early endosome and the Hsp90-chaperoned peptide was processed and bound to MHC class I molecules through an endosome-recycling pathway. Our data indicate that targeting of the antigen to a static early endosome by Hsp90 is essential for efficient cross-presentation.

  DOI PubMed

• A Novel CIC-FOXO4 Gene Fusion in Undifferentiated Small Round Cell Sarcoma A Genetically Distinct Variant of Ewing-like Sarcoma

  Shintaro Sugita, Yasuhito Arai, Akiko Tonooka, Natsuko Hama, Yasushi Totoki, Tomoki Fujii, Tomoyuki Aoyama, Hiroko Asanuma, Tomohide Tsukahara, Mitsunori Kaya, Tatsuhiro Shibata, Tadashi Hasegawa

  AMERICAN JOURNAL OF SURGICAL PATHOLOGY ( LIPPINCOTT WILLIAMS & WILKINS )  38 ( 11 ) 1571 - 1576  2014年11月  [査読有り]

  　概要を見る

  Differential diagnosis of small round cell sarcomas (SRCSs) grouped under the Ewing sarcoma family of tumors (ESFT) can be a challenging situation for pathologists. Recent studies have revealed that some groups of Ewing-like sarcoma show typical ESFT morphology but lack any EWSR1-ETS gene fusions. Here we identified a novel gene fusion, CIC-FOXO4, in a case of Ewing-like sarcoma with a t(X; 19)(q13;q13.3) translocation. The patient was a 63-year-old man who had an asymptomatic, 30-mm, well-demarcated, intramuscular mass in his right posterior neck, and imaging findings suggested a diagnosis of high-grade sarcoma. He was treated with complete resection and subsequent radiotherapy and chemotherapy. He was alive without local recurrence or distant metastasis 6 months after the operation. Histologic examination revealed SRCS with abundant desmoplastic fibrous stroma suggesting a desmoplastic small round cell tumor. Immunohistochemical analysis showed weak to moderate and partial staining for MIC2 (CD99) and WT1, respectively. High-throughput transcriptome sequencing revealed a gene fusion, and the genomic rearrangement between the CIC and FOXO4 genes was identified by fluorescence in situ hybridization. Aside from the desmoplastic stroma, the CIC-FOXO4 fusion sarcoma showed morphologic and immunohistochemical similarity to ESFT and Ewing-like sarcomas, including the recently described CIC-DUX4 fusion sarcoma. Although clinicopathologic analysis with additional cases is necessary, we conclude that CIC-FOXO4 fusion sarcoma is a new type of Ewing-like sarcoma that has a specific genetic signature. These findings have important implications for the differential diagnosis of SRCS.

  DOI PubMed

• Specific Targeting of a Naturally Presented Osteosarcoma Antigen, Papillomavirus Binding Factor Peptide, Using an Artificial Monoclonal Antibody

  Tomohide Tsukahara, Makoto Emori, Kenji Murata, Takahisa Hirano, Norihiro Muroi, Masanori Kyono, Shingo Toji, Kazue Watanabe, Toshihiko Torigoe, Vitaly Kochin, Hiroko Asanuma, Hiroshi Matsumiya, Keiji Yamashita, Tetsuo Himi, Shingo Ichimiya, Takuro Wada, Toshihiko Yamashita, Tadashi Hasegawa, Noriyuki Sato

  JOURNAL OF BIOLOGICAL CHEMISTRY ( AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC )  289 ( 32 ) 22035 - 22047  2014年08月  [査読有り]

  　概要を見る

  Osteosarcoma is a rare but highly malignant tumor occurring most frequently in adolescents. The prognosis of non-responders to chemotherapy is still poor, and new treatment modalities are needed. To develop peptide-based immunotherapy, we previously identified autologous cytotoxic T lymphocyte-defined osteosarcoma antigen papillomavirus binding factor (PBF) in the context of HLA-B55 and the cytotoxic T lymphocyte epitope (PBF A2.2) presented by HLA-A2. PBF and HLA class I are expressed in similar to 90 and 70% of various sarcomas, respectively. However, the expression status of peptide PBF A2.2 presented by HLA-A2 on osteosarcoma cells has remained unknown because it is difficult to generate a specific probe that reacts with the HLA.peptide complex. For detection and qualification of the HLA-A*02:01.PBF A2.2 peptide complex on osteosarcoma cells, we tried to isolate a single chain variable fragment (scFv) antibody directed to the HLA-*A0201.PBF A2.2 complex using a naive scFv phage display library. As a result, scFv clone D12 with high affinity (K-D = 1.53 x 10(-9) M) was isolated. D12 could react with PBF A2.2 peptide-pulsed T2 cells and HLA-A2+PBF+ osteosarcoma cell lines and simultaneously demonstrated that the HLA.peptide complex was expressed on osteosarcoma cells. In conclusion, scFv clone D12 might be useful to select candidate patients for PBF A2.2 peptide-based immunotherapy and develop antibody-based immunotherapy.

  DOI PubMed

• Diagnostic utility of NCOA2 fluorescence in situ hybridization and Stat6 immunohistochemistry staining for soft tissue angiofibroma and morphologically similar fibrovascular tumors

  Shintaro Sugita, Tomoyuki Aoyama, Kei Kondo, Yoshiko Keira, Jiro Ogino, Katsuya Nakanishi, Mitsunori Kayo, Makoto Emori, Tomohide Tsukahara, Hisaya Nakajima, Masayuki Takagi, Tadashi Hasegawa

  HUMAN PATHOLOGY ( W B SAUNDERS CO-ELSEVIER INC )  45 ( 8 ) 1588 - 1596  2014年08月  [査読有り]

  　概要を見る

  Soft tissue angiofibroma (STA), a recently suggested new histologic entity, is a benign flbrovascular soft tissue tumor composed of bland spindle-shaped tumor cells with abundant collagenous to myxoid stroma and branching small vessels. The lesion has a characteristic AHRR-NCOA2 fusion gene derived from chromosomal translocation of t(5;8)(p15;q13). However, morphologically similar tumors containing abundant flbrovascular and myxoid stroma can complicate diagnosis. We designed an original DNA probe for detecting NCOA2 split signals on fluorescence in situ hybridization (FISH) and estimated its utility with 20 fibrovascular tumors: 4 each of STAs, solitary fibrous tumors (SFTs), and cellular angiofibromas and 3 each of low-grade myxofibrosarcomas, myxoid liposarcomas, and low-grade fibromyxoid sarcomas. We also performed FISH for 13q14 deletion and immunohistochemistry (IHC) staining for estrogen receptor, progesterone receptor, retinoblastoma protein, and MUC-4 expression. Furthermore, MC for Stat6 was conducted in the 20 cases analyzed by FISH and in an additional 26 SFTs. We found moderate to strong nuclear Stat6 expression in all SFTs but no expression in the other tumors. Both estrogen receptor and progesterone receptor expressions were observed in STAs, SFTs, and cellular angiofibromas. Expression of retinoblastoma protein was found in less than 10% of cells in all tumor types except myxoid liposarcoma. The low:grade fibromyxoid sarcomas were strongly positive for MUC-4. All STAs showed NCOA2 split signals on FISH. All tumors, regardless of histologic type, had 13q14 deletion. The NCOA2 FISH technique is a practical method for confirming STA diagnosis. The combination of NCOA2 FISH and Stat6 IHC proved effective for the differential diagnosis of STA, even when using small biopsy specimens. (C) 2014 Elsevier Inc. All rights reserved.

  DOI PubMed

• Heat shock protein DNAJB8 is a novel target for immunotherapy of colon cancer-initiating cells

  Rena Morita, Satoshi Nishizawa, Toshihiko Torigoe, Akari Takahashi, Yasuaki Tamura, Tomohide Tsukahara, Takayuki Kanaseki, Alice Sokolovskaya, Vitaly Kochin, Toru Kondo, Satoshi Hashino, Masahiro Asaka, Isao Hara, Yoshihiko Hirohashi, Noriyuki Sato

  Cancer Science ( Blackwell Publishing Ltd )  105 ( 4 ) 389 - 395  2014年  [査読有り]

  　概要を見る

  The aim of the present study was to establish cancer stem-like cell/cancer-initiating cell (CSC/CIC)-targeting immunotherapy. The CSC/CIC are thought to be essential for tumor maintenance, recurrence and distant metastasis. Therefore they are reasonable targets for cancer therapy. In the present study, we found that a heat shock protein (HSP) 40 family member, DnaJ (Hsp40) homolog, subfamily B, member 8 (DNAJB8), is preferentially expressed in CSC/CIC derived from colorectal cancer (CRC) cells rather than in non-CSC/CIC. Overexpression of DNAJB8 enhanced the expression of stem cell markers and tumorigenicity, indicating that DNAJB8 has a role in CRC CSC/CIC. A DNAJB8-specific cytotoxic T lymphocyte (CTL) response could be induced by a DNAJB8-derived antigenic peptide. A CTL clone specific for DNAJB8 peptide showed higher killing activity to CRC CSC/CIC compared with non-CSC/CIC, and CTL adoptive transfer into CRC CSC/CIC showed an antitumor effect in vivo. Taken together, the results indicate that DNAJB8 is expressed and has role in CRC CSC/CIC and that DNAJB8 is a novel target of CRC CSC/CIC-targeting immunotherapy. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  DOI PubMed

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• ビギナーズセミナー7 わかる！がん免疫とがん抗原

  塚原 智英

  日本臨床免疫学会会誌 ( 日本臨床免疫学会 )  37 ( 4 ) 299 - 299  2014年

  　概要を見る

  癌免疫は，癌に対する免疫応答の理解と癌の免疫制御を目指す学問であり，癌抗原の同定によって飛躍的に発展した．よって癌免疫の理解には癌抗原の理解が重要である．癌免疫の存在は1990年代に自家細胞傷害性T細胞（CTL）クローンに認識されるヒト癌抗原のクローニングにより，主にメラノーマで証明された．これらの発見にはforward immunology approachといわれる腫瘍反応性ヒト自家CTLクローンの樹立とcDNAライブラリ発現クローニング法の開発が大きく貢献した．さらに既知の候補抗原からCTLエピトープを求めるreverse immunology approachも盛んに行われ，メラノーマ以外からも多くの抗原が同定された．これらの知見はペプチドワクチンや抗原特異的リンパ球大量輸注療法の開発につながっている．また昨年は抗CTLA-4抗体や抗PD-1抗体などのチェックポイント抗体による活性化T細胞制御がメラノーマに対して有効性を示して一世を風靡した．チェックポイント抗体がメラノーマでよく効いた理由として（1）癌抗原が皮膚のランゲルハンス細胞に取り込まれてCTLを効率よくプライムできる，（2）高い免疫原性を持つ変異抗原が多く発現してる点が重要と考えられる．今後は高い腫瘍特異性をもち，かつ造腫瘍能を制御する癌の根源に迫る癌抗原の同定が重要となる．また自家CTLが認識する抗原の同定は，時に我々の想像がおよばないようなセレンディピティを与えてくれる．

  DOI CiNii

• 合同シンポジウム2-5  がんワクチン創薬への道程：がん抗原の同定から臨床試験まで

  鳥越 俊彦, 廣橋 良彦, 塚原 智英, 島 宏彰, 水口 徹, 平田 公一, 佐藤 昇志

  日本臨床免疫学会会誌 ( 日本臨床免疫学会 )  36 ( 5 ) 313 - 313  2013年

  　概要を見る

  我々は過去20年以上にわたってヒトがん抗原の同定とそれに対する免疫応答の分子機構を解明し，Survivinをはじめとする10種類以上のヒトがん抗原とそのHLA class I拘束性T細胞エピトープの構造を明らかにしてきた．抗原ペプチドを用いて患者の末梢血リンパ球を刺激すると，ペプチド特異的細胞障害性T細胞が誘導される．平成14年度からSVN-2Bペプチドワクチンの臨床試験を開始．平成23年度からは医師主導治験を実施している．Tetramerを用いた免疫モニタリングの結果，ペプチド特異的T細胞の頻度と抗腫瘍効果との間に相関性が見出された．また，インターフェロンの併用によって臨床効果が増強することが判明した．10月には進行膵臓がんに対する第2相試験（二重盲検試験）をスタートする．  一方で我々は，ヒトの固形腫瘍細胞株からがん幹細胞（CSC）を分離することに成功し，現在CSC特異抗原の探索を実施している．がん幹細胞は，長寿命・高い造腫瘍能力・高い遊走能・抗がん剤耐性などの特性を有することから，がん再発と転移の根幹をなす細胞であると推察されている．CSC特異抗原はどのような分子か，CSC特異的細胞障害性T細胞の誘導とCSC標的治療モデル等を紹介し，がん幹細胞標的ワクチン創薬に向けての歩みと展望についても議論したい．

  DOI CiNii

• 中高年者の橈骨遠位端骨折変形治癒に対する矯正骨切り術 : 橈骨 closing wedge osteotomy と尺骨短縮術の併用

  和田 卓郎, 磯貝 哲, 塚原 智英, 相木 比古乃, 金谷 耕平, 青木 光広

  日本手の外科学会雑誌 = The Journal of Japanese Society for Surgery of the Hand   21 ( 2 ) 61 - 64  2004年10月

  CiNii

• 難治性テニス肘のMRI所見と手術所見の検討

  青木 光広, 佐藤 攻, 塚原 智英, 和田 卓郎, 石井 清一

  日本手の外科学会雑誌 = The Journal of Japanese Society for Surgery of the Hand   18 ( 5 ) 728 - 732  2002年02月

  CiNii

• 手根管症候群における母指球部の知覚評価

  和田 卓郎, 磯貝 哲, 塚原 智英, 石井 清一, 青木 光広

  日本手の外科学会雑誌 = The Journal of Japanese Society for Surgery of the Hand   18 ( 5 ) 721 - 723  2002年02月

  CiNii

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