Blocking the arylhydrocarbon receptor for cancer immunotherapy

• Project/Area Number: 15H06247
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Tumor therapeutics
• Research Institution: Gifu University
• Principal Investigator: Ninomiya Soranobu 岐阜大学, 医学部附属病院, 助教 (90444281)
• Project Period (FY): 2015-08-28 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 腫瘍免疫 / アリルハイドロカーボン受容体 / キヌレニン / 癌 / 免疫

Outline of Final Research Achievements

IDO is an intracellular enzyme proceed the essential amino acid tryptophan metabolism. Accumulation of tryptophan derivatives such as kynurenine blocks antigen-specific T-cell proliferation and induces T-cell death. A recent study indicated that kynurenine was an endogenous ligand of aryl hydrocarbon receptor (AhR). We collected PBMCs from healthy blood donors, and bone marrow samples from multiple myeloma patients at first diagnosis. The cells were activated with anti-CD3 and anti-CD28 Abs. We measured the expression of AhR in activated T-cells using by flow cytometry.Kynurenine produced by IDO, induce inhibitory signal in T-cells through the AhR. Anti-PD-1 and anti-CTLA-4 therapies, which block directly the inhibitory signal in T-cells, have been getting some clinical benefits against such as melanoma and Hodgkin lymphoma. Therefore, the AhR in T cells might be a target for IDO-positive hematological malignancies.

Research Products

• [Journal Article] Serum concentrations of l-kynurenine predict clinical outcomes of patients with peripheral T-cell lymphoma, not otherwise specified. (2016)
  • Author(s): Shibata Y, Hara T, Matsumoto T, Nakamura N, Nakamura H, Ninomiya S, Kitagawa J, Goto N, Nannya Y, Ito H, Kito Y, Miyazaki T, Takeuchi T, Saito K, Seishima M, Takami T, Moriwaki H, Shimizu M, Tsurumi H.
  • Journal Title: Hematological Oncology Volume: - Issue: 4 Pages: 637-644
  • DOI: 10.1002/hon.2318
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic value of the combination of serum l-kynurenine level and indoleamine 2,3-dioxygenase mRNA expression in acute myeloid leukemia. (2016)
  • Author(s): Hara T, Matsumoto T, Shibata Y, Nakamura N, Nakamura H, Ninomiya S, Kitagawa J, Nannya Y, Shimizu M, Ito H, Saito K, Tsurumi H.
  • Journal Title: Leukemia Lymphoma Volume: 57(9) Issue: 9 Pages: 2208-2211
  • DOI: 10.3109/10428194.2015.1128541
  • Peer Reviewed
• [Journal Article] Prognostic value of the combination of serum l-kynurenine level and indoleamine 2,3-dioxygenase mRNA expression in acute myeloid leukemia. (2016)
  • Author(s): Hara T, Matsumoto T, Shibata Y, Nakamura N, Nakamura H, Ninomiya S, Kitagawa J, Nannya Y, Shimizu M, Ito H, Saito K, Tsurumi H.
  • Journal Title: Hematology Oncology Volume: 21 Issue: 3 Pages: 1-4
  • DOI: 10.1002/hon.2285
  • Peer Reviewed
• [Journal Article] The Role of Indoleamine 2,3-Dioxygenase in Diethylnitrosamine-Induced Liver Carcinogenesis (2016)
  • Author(s): Shibata Y, Hara T, Nagano J, Nakamura N, Ohno T, Ninomiya S, Ito H, Tanaka T, Saito K, Seishima M, Shimizu M, Moriwaki H, Tsurumi H
  • Journal Title: Leukemia Lymphoma Volume: 11 Issue: 1 Pages: 4-11
  • DOI: 10.1371/journal.pone.0146279
  • Peer Reviewed
• [Presentation] 腫瘍微小環境中Ｔ細胞におけるアリルハイドロカーボン受容体の重要性 (2016)
  • Author(s): 二宮 空暢 中村 信彦 北川 順一 原 武志 清水 雅仁 鶴見 寿
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 神奈川県・横浜
• [Presentation] The Roles of Aryl Hydrocarbon Receptor in T cells at IDO-positive Tumor Microenvironment (2016)
  • Author(s): 二宮 空暢 中村 信彦 北川 順一 原 武志 清水 雅仁 鶴見 寿
  • Organizer: 第58回アメリカ血液学会総会
  • Place of Presentation: アメリカ・サンディエゴ
  • Int'l Joint Research
• [Remarks] 岐阜血液疾患研究グループホームページ
  • URL: http://seesaawiki.jp/ghsp/
• [Remarks] Gifu Hematology Study Group
  • URL: http://seesaawiki.jp/ghsp/