Elucidation of mechanisms underlying lymphoproliferative disorders for targeted therapy in patients with autoimmune diseases

• Project/Area Number: 16K08683
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Hokkaido University
• Principal Investigator: Hatanaka Kanako 北海道大学, 大学病院, 特任講師 (10399834)
• Co-Investigator(Kenkyū-buntansha): 畑中 豊 北海道大学, 大学病院, 特任准教授 (30589924)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: リンパ増殖性疾患 / 自己免疫性疾患 / びまん性大細胞型B細胞リンパ腫 / 腫瘍微小環境 / 自己免疫性疾患関連リンパ増殖性疾患 / 治療効果予測 / DNAメチル化 / 病理学 / 癌 / ゲノム

Outline of Final Research Achievements

In this study, we analyzed the tumor microenvironment of diffuse large B-cell lymphoma (DLBCL) in patients with autoimmune disease (AID) treated with immunosuppressants. The number of patients with increased FOXP3-positive regulatory T-cell infiltration was significantly higher in the AID group than in the non-AID (nAID) group. Gene expression profiling revealed a significant difference in 7 genes between AID and nAID groups. In addition, among the 24 differentially expressed genes between the AID group with and without EBV infection, 4 genes including TNFRSF8 (CD30) showed increased expression. These results further our understanding of the tumor microenvironment and can be useful for the development of therapeutic strategies for AID-DLBCL patients in the future.

Academic Significance and Societal Importance of the Research Achievements

本研究ではAID-DLBCLの腫瘍微小環境に着目し、nAID-DLBCLとの比較やEBV感染の有無を含めた解析を行った。腫瘍微小環境の浸潤細胞の密度に大きな差異は認められなかったが、遺伝子発現プロファイル解析では複数の遺伝子発現に違いがみられたことから、形態的は大きな差異のない両者においても腫瘍微小環境に違いがみられることが判明し、かつその中の高発現を示す遺伝子をターゲットにした治療薬がすでに他の腫瘍で臨床導入されていることから、本疾患における新たな治療法の可能性を見出した。

Research Products

• [Journal Article] Prognostic impact of CD8+ T cell distribution and Its association with the HLA class I expression in intrahepatic cholangiocarcinoma (2020)
  • Author(s): Asahi Y, Hatanaka KC, Hatanaka Y, Kamiyama T, Orimo T, Shimada S, Nagatsu A, Sakamoto Y, Kamachi H, Kobayashi N, Fukai M, Taketomi A.
  • Journal Title: Surg Today Volume: Online ahead of print Issue: 8 Pages: 931-940
  • DOI: 10.1007/s00595-020-01967-y
  • Peer Reviewed
• [Journal Article] Prognostic relevance of tertiary lymphoid organs following neoadjuvant chemoradiotherapy in pancreatic ductal adenocarcinoma (2019)
  • Author(s): Kuwabara Shota、Tsuchikawa Takahiro、Nakamura Toru、Hatanaka Yutaka、Hatanaka Kanako C.、Sasaki Katsunori、Ono Masato、Umemoto Kazufumi、Suzuki Tomohiro、Sato Osamu、Hane Yuma、Nakanishi Yoshitsugu、Asano Toshimichi、Ebihara Yuma、Kurashima Yo、Noji Takehiro、Murakami Soichi、Okamura Keisuke et al.
  • Journal Title: Cancer Science Volume: 110 Issue: 6 Pages: 1853-1862
  • DOI: 10.1111/cas.14023
  • NAID: 40021983711
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative detection of IKZF1 deletion by digital PCR in patients with acute lymphoblastic leukemia (2018)
  • Author(s): Hashiguchi J, Onozawa M, Okada K, Amano T, Hatanaka KC, Nishihara H, Sato N, Teshima T
  • Journal Title: Int J Lab Hematol Volume: 41 Issue: 2
  • DOI: 10.1111/ijlh.12945
  • Peer Reviewed
• [Journal Article] 胸水中にIgG4陽性形質細胞浸潤を証明できた、IgG4関連疾患と考えられる1例 (2018)
  • Author(s): 吹矢美佳，丸川克司，清水智宏，宮越里絵，安孫子光春，畑中佳奈子，三橋智子，松野吉宏
  • Journal Title: 日本臨床細胞学会雑誌 Volume: 59 Pages: 50-55
  • NAID: 130006405500
  • Peer Reviewed
• [Journal Article] Re-infection of toxoplasma gondii after HSCT presenting lymphadenopathy resembling recurrence of lymphoma (2018)
  • Author(s): Hashiguchi J, Onozawa M, Naka T, Hatanaka KC, Shiratori S, Sugita J, Fujimoto K, Matsuno Y, Teshima T
  • Journal Title: Transpl Infect Dis Volume: 20 Issue: 3
  • DOI: 10.1111/tid.12892
  • Peer Reviewed
• [Journal Article] Cytopathologic findings of cell block materials from the vitreous: Diagnostic distinction between intraocular lymphoma and non-lymphomatous diseases (2017)
  • Author(s): Kanno-Okada H, Takakuwa E, Tagawa Y, Kase S, Hatanaka KC, Hatanaka Y, Namba K, Mitsuhashi T, Matsuno Y.
  • Journal Title: Pathol Int Volume: 67 Issue: 7 Pages: 342-349
  • DOI: 10.1111/pin.12551
  • NAID: 120006484244
  • Peer Reviewed
• [Journal Article] Subcutaneous panniculitis-like T-cell lymphoma with haemophagocytic syndrome during tocilizumab therapy for juvenile idiopathic arthritis (2017)
  • Author(s): Nakamura H, Sugai T, Kato M, Hatanaka KC, Atsumi T
  • Journal Title: Clin Exp Rheumatol Volume: 35 Pages: 174-174
  • Peer Reviewed
• [Journal Article] Late-onset skin involvement on the forehead in multicentric Castleman disease (2017)
  • Author(s): Sato K, Shinkuma S, Fujimoto K, Hatanaka KC, Ujiie H, Nomura T, Fujita Y, Abe R, Matsuno Y, Shimizu H
  • Journal Title: Int J Dermatol Volume: 56 Issue: 7
  • DOI: 10.1111/ijd.13559
  • Peer Reviewed
• [Journal Article] Diffuse large B-cell lymphoma with a bulky mass in the cranial vault (2017)
  • Author(s): Kanaya M, Endo T, Hashimoto D, Endo S, Takemura R, Okada K, Hatanaka KC, Matsuno Y, Teshima T
  • Journal Title: Int J Hematol Volume: 106 Issue: 2 Pages: 147-148
  • DOI: 10.1007/s12185-017-2229-x
  • Peer Reviewed
• [Journal Article] A pilot study of operational tolerance with a regulatory T cell-based cell therapy in living donor liver transplantation. (2016)
  • Author(s): ①Todo S, Yamashita K, Goto R, Zaitsu M, Nagatsu A, Oura T, Watanabe M, Aoyagi T, Suzuki T, Shimamura T, Kamiyama T, Sato N, Sugita J, Hatanaka K, Bashuda H, Habu S, Demetris AJ, Okumura K
  • Journal Title: Hepatology Volume: 00 Issue: 2 Pages: 00-00
  • DOI: 10.1002/hep.28459
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning for mycosis fungoides and Sezary syndrome. (2014)
  • Author(s): Shiratori S, Fujimoto K, Nishimura M, Hatanaka KC, Kosugi-Kanaya M, Okada K, Sugita J, Shigematsu A, Hashimoto D, Endo T, Kondo T, Abe R, Hashino S, Matsuno Y, Shimizu H, Teshima T.
  • Journal Title: Hematol Oncol Volume: Epub Ahead of Print Issue: 1 Pages: 9-16
  • DOI: 10.1002/hon.2162
  • NAID: 120005981361
  • Peer Reviewed / Open Access
• [Presentation] 自己免疫性疾患患者に発生するびまん性大細胞型B細胞リンパ腫の微小環境の検討 (2019)
  • Author(s): 畑中 佳奈子，畑中 豊，藤本 勝也，奥村 麻美，南家 綾江，津矢田 明泰，齋 藤 辰朗，豊嶋 崇徳，松野 吉宏
  • Organizer: 第108回日本病理学会総会
• [Presentation] 初回治療から18年後に生じた多臓器進展を伴うホジキンリンパ腫の一剖検例 (2019)
  • Author(s): 五味川 龍，杉野 弘和，白鳥 聡一，石田 雄介，王 磊，畑中 佳奈子，松野 吉宏，豊嶋 崇徳，田中 伸哉
  • Organizer: 第108回日本病理学会総会
• [Presentation] 血管筋脂肪腫；結節性硬化症との関連を中心に (2016)
  • Author(s): 畑中 佳奈子，宮島 直人，畑中 豊，篠原 信雄，松野 吉宏
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2016-05-12
• [Presentation] 非小細胞肺癌におけるPD-L1とAKR1B10発現の関連性に関する検討 (2016)
  • Author(s): 桑原 健，畑中 豊，岡田 宏美，清水 知浩，奥村 麻美，平野 裕子， 畑中 佳奈子，樋田 泰浩，加賀 基知三，松野 吉宏
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2016-05-12
• [Book] マントル細胞リンパ腫（「リンパ腫アトラス」第5版） (2018)
  • Author(s): 畑中佳奈子、松野吉宏
  • Publisher: 株式会社文光堂
  • ISBN: 9784830604799
• [Book] 原発性縦隔（胸腺）大細胞型B細胞リンパ腫（「リンパ腫アトラス」第5版） (2018)
  • Author(s): 畑中佳奈子、松野吉宏
  • Publisher: 株式会社文光堂
  • ISBN: 9784830604799