移植後再発白血病におけるHLAの翻訳後修飾を介した免疫逃避機構の解明

• Project/Area Number: 23K07853
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: The University of Tokyo
• Principal Investigator: 小沼 貴晶 東京大学, 医科学研究所, 准教授 (00709553)
• Project Period (FY): 2023-04-01 – 2026-03-31
• Project Status: Granted (Fiscal Year 2023)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2025: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2024: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2023: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 同種造血細胞移植 / 白血病 / 再発 / GVL効果 / HLA / 移植片対白血病効果

Outline of Research at the Start

急性骨髄性白血病を含む造血器腫瘍に対する同種造血細胞移植は、移植片に含まれるCD8+T細胞を中心とした免疫細胞により誘導される移植片対白血病(Graft-versus-leukemia：GVL)効果に基づくがん免疫療法の一つである。GVL効果からの逃避機構として、遺伝子の変異や喪失に伴うHLA消失が30％程度に認められるが、それ以外のメカニズムは明らかとされていない。本研究では、GVL効果からの逃避機構が、遺伝子の変異や喪失に伴わず、HLAタンパクの翻訳後修飾の異常が関与している可能性について検証を行う。

Outline of Annual Research Achievements

急性骨髄性白血病を含む造血器腫瘍に対する同種造血細胞移植は、移植片に含まれるCD8+T細胞やNK細胞を中心とした免疫細胞により誘導される移植片対白血病(Graft-versus-leukemia：GVL)効果に基づくがん免疫療法の一つである。同種造血細胞移植後の白血病の再発は、同種造血細胞移植による治療不応として最も頻度が高く、30%程度に認められる。これは白血病細胞が免疫監視機構から逃避することによる機序が主要因の一つとされている。GVL効果からの逃避機構として、遺伝子の変異や喪失に伴うHLA消失が30％程度に認められるが、それ以外のメカニズムは明らかとされていない。本研究では、GVL効果からの逃避機構が、遺伝子の変異や喪失に伴わず、HLAタンパクの翻訳後修飾の異常が関与している可能性について検証を行う。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

今年度は、移植後再発した急性骨髄性白血病において、移植前後の臨床検体を用いて、シングルセルRNAシーケンスを行い、現在データ解析中であり、移植前後における免疫監視機構の詳細を明らかにする予定である。今年度は、適切に研究が進行している。

Strategy for Future Research Activity

移植後再発の急性骨髄性白血病による免疫回避機構の解明に繋がる遺伝子、さらに翻訳後修飾に関与しうる遺伝子を同定することで、新規治療標的の解明に繋げる予定である。

Research Products

• [Journal Article] Allogeneic transplantation of bone marrow versus peripheral blood stem cells from HLA-identical sibling donors for hematological malignancies in 6064 adults from 2003 to 2020: different impacts on survival according to time period (2024)
  • Author(s): Konuma Takaaki、Miyao Kotaro、Nakasone Hideki、Ouchi Fumihiko、Fukuda Takahiro、Tanaka Masatsugu、Ozawa Yukiyasu、Ota Shuichi、Kawakita Toshiro、Uchida Naoyuki、Sawa Masashi、Katayama Yuta、Hiramoto Nobuhiro、Eto Tetsuya、Ichinohe Tatsuo、Atsuta Yoshiko、Kanda Junya
  • Journal Title: Cytotherapy Volume: In press Issue: 8 Pages: 910-920
  • DOI: 10.1016/j.jcyt.2024.03.489
  • Peer Reviewed
• [Journal Article] <scp>RhD</scp> mismatch does not affect haematopoietic recovery, graft‐versus‐host disease and survival in allogeneic haematopoietic cell transplantation: A Japanese registry‐based study (2024)
  • Author(s): Konuma Takaaki、Uchida Naoyuki、Takeda Wataru、Doki Noriko、Yoshihara Satoshi、Nishida Tetsuya、Kuriyama Takuro、Tanaka Masatsugu、Ohigashi Hiroyuki、Nakamae Hirohisa、Katayama Yuta、Ota Shuichi、Hashii Yoshiko、Ishimaru Fumihiko、Fukuda Takahiro、Ohbiki Marie、Atsuta Yoshiko
  • Journal Title: Vox Sanguinis Volume: In press Issue: 6 Pages: 612-618
  • DOI: 10.1111/vox.13610
  • Peer Reviewed / Open Access
• [Journal Article] Machine Learning Prediction Model for Neutrophil Recovery after Unrelated Cord Blood Transplantation (2024)
  • Author(s): Kuwatsuka Yachiyo、Kasajima Rika、Yamaguchi Rui、Uchida Naoyuki、Konuma Takaaki、Tanaka Masatsugu、Shingai Naoki、Miyakoshi Shigesaburo、Kozai Yasuji、Uehara Yasufumi、Eto Tetsuya、Toyosaki Masako、Nishida Tetsuya、Ishimaru Fumihiko、Kato Koji、Fukuda Takahiro、Imoto Seiya、Atsuta Yoshiko、Takahashi Satoshi
  • Journal Title: Transplantation and Cellular Therapy Volume: 30 Issue: 4 Pages: 444.e1-444.e11
  • DOI: 10.1016/j.jtct.2024.02.001
  • Peer Reviewed
• [Journal Article] The effect of center experience on allogeneic hematopoietic cell transplantation outcomes in acute myeloid leukemia (2024)
  • Author(s): Yanada Masamitsu、Yano Shingo、Kuwatsuka Yachiyo、Kawamura Koji、Fukuda Takahiro、Ichinohe Tatsuo、Hashii Yoshiko、Goto Hideki、Kato Koji、Ishimaru Fumihiko、Sato Atsushi、Onizuka Makoto、Matsuo Keitaro、Ito Yuri、Yanagisawa Atsumi、Ohbiki Marie、Tabuchi Ken、Atsuta Yoshiko、Kanda Junya、Konuma Takaaki
  • Journal Title: Bone Marrow Transplantation Volume: 59 Issue: 4 Pages: 541-549
  • DOI: 10.1038/s41409-024-02222-5
  • Peer Reviewed
• [Journal Article] Donor NKG2D rs1049174 polymorphism predicts hematopoietic recovery and event-free survival after single-unit cord blood transplantation in adults (2024)
  • Author(s): Konuma Takaaki、Hamatani-Asakura Megumi、Monna-Oiwa Maki、Kato Seiko、Isobe Masamichi、Yokoyama Kazuaki、Nannya Yasuhito、Takahashi Satoshi
  • Journal Title: Bone Marrow Transplantation Volume: 59 Issue: 4 Pages: 566-568
  • DOI: 10.1038/s41409-024-02217-2
  • Peer Reviewed
• [Journal Article] Low urinary sodium-to-potassium ratio in the early phase following single-unit cord blood transplantation is a predictive factor for poor non-relapse mortality in adults (2024)
  • Author(s): Takano Kosuke、Monna-Oiwa Maki、Isobe Masamichi、Kato Seiko、Takahashi Satoshi、Nannya Yasuhito、Konuma Takaaki
  • Journal Title: Scientific Reports Volume: 14 Issue: 1 Pages: 1413-1413
  • DOI: 10.1038/s41598-024-51748-7
  • Peer Reviewed / Open Access
• [Journal Article] Association of individual comorbidities with outcomes in allogeneic hematopoietic cell transplantation from unrelated adult donors versus unrelated cord blood: A study on behalf of the Donor/Source and Transplant Complications Working Groups of the Japanese Society for Transplantation and Cellular Therapy (2024)
  • Author(s): Konuma Takaaki、Harada Kaito、Shinohara Akihito、Uchida Naoyuki、Shingai Naoki、Ito Ayumu、Ozawa Yukiyasu、Tanaka Masatsugu、Sawa Masashi、Onizuka Makoto、Katayama Yuta、Hiramoto Nobuhiro、Nakano Nobuaki、Kimura Takafumi、Kanda Yoshinobu、Fukuda Takahiro、Atsuta Yoshiko、Nakasone Hideki、Kanda Junya
  • Journal Title: American Journal of Hematology Volume: 99 Issue: 2 Pages: 263-273
  • DOI: 10.1002/ajh.27174
  • Peer Reviewed / Open Access
• [Journal Article] Scoring system for optimal cord blood unit selection for single cord blood transplantation (2024)
  • Author(s): Watanabe Mizuki、Konuma Takaaki、Imahashi Nobuhiko、Terakura Seitaro、Kanda Junya et al.
  • Journal Title: Cytotherapy Volume: 26 Issue: 3 Pages: 286-298
  • DOI: 10.1016/j.jcyt.2023.12.001
  • Peer Reviewed
• [Journal Article] HLA-Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplantation Cyclophosphamide versus HLA-Matched Unrelated Donor Transplantation for Myelodysplastic Syndrome. (2024)
  • Author(s): Nakaya Y, Koh H, Konuma T, Shimomura Y, Ishiyama K, Itonaga H, Hino M, Doki N, Nishida T, Ohigashi H, Matsuoka KI, Kanda Y, Maruyama Y, Sawa M, Eto T, Hiramoto N, Fukuda T, Atsuta Y, Nakamae H.
  • Journal Title: Transplantation and Cellular Therapy. Volume: 30 Issue: 3 Pages: 316.e1-316.e12
  • DOI: 10.1016/j.jtct.2023.10.021
  • Peer Reviewed
• [Journal Article] Effect of Conditioning Regimens and Graft-versus-Host Disease Prophylaxis on the Outcomes of Umbilical Cord Blood Transplantation Performed with Cyclophosphamide/Total Body Irradiation-Based Regimens (2024)
  • Author(s): Imahashi Nobuhiko、Kurita Naoki、Konuma Takaaki、Takahashi Satoshi、Nishida Tetsuya、Tanaka Masatsugu、Nakamae Hirohisa、Kawakita Toshiro、Ota Shuichi、Doki Noriko、Onishi Yasushi、Sawa Masashi、Ozeki Kazutaka、Hiramoto Nobuhiro、Onizuka Makoto、Ishimaru Fumihiko、Ichinohe Tatsuo、Atsuta Yoshiko、Kanda Junya
  • Journal Title: Transplantation and Cellular Therapy Volume: 30 Issue: 3 Pages: 318.e1-318.e11
  • DOI: 10.1016/j.jtct.2023.12.004
  • Peer Reviewed
• [Journal Article] Comparison of Allogeneic Transplant Outcomes Between Matched Sibling Donors and Alternative Donors in Patients Over 50 Years of Age with Acute Myeloid Leukemia: 8/8 Allele-Matched Unrelated Donors and Unrelated Cord Blood Provide Better Leukemia-Free Survival Compared with Matched Sibling Donors During Nonremission Status (2024)
  • Author(s): Konuma T, Yamasaki S, Ishiyama K, Mizuno S, Hayashi H, Uchida N, Shimabukuro M, Tanaka M, Kuriyama T, Onizuka M, Ishiwata K, Sawa M, Tanaka T, Ohigashi H, Fujiwara SI, Matsuoka KI, Ota S, Nishida T, Kanda Y, Fukuda T, Atsuta Y, Nakasone H, Yanada M
  • Journal Title: Transplantation and Cellular Therapy Volume: 30 Issue: 2 Pages: 215.e1-215.e18
  • DOI: 10.1016/j.jtct.2023.12.002
  • Peer Reviewed
• [Journal Article] Hematopoietic stem cell transplantation from haploidentical offspring donors using post-transplant cyclophosphamide versus human leukocyte antigen-matched siblings in older patients with myelodysplastic syndrome. (2024)
  • Author(s): Shimomura Y, Kitamura T, Konuma T, Nakaya Y, Doki N, Sawa M, Nakamae H, Eto T, Nishida T, Ohigashi H, Ota S, Onizuka M, Hiramoto N, Kawakita T, Kanda J, Ichinohe T, Atsuta Y, Itonaga H.
  • Journal Title: American Journal of Hematology. Volume: 99 Issue: 2
  • DOI: 10.1002/ajh.27160
  • Peer Reviewed / Open Access
• [Journal Article] Prevalence and factors of polypharmacy among disease-free survivors of adults after allogeneic hematopoietic cell transplantation (2023)
  • Author(s): Miyashita Eita、Sugihara Nozomi、Tanaka Miho、Iwasaki Hiromi、Monna-Oiwa Maki、Isobe Masamichi、Kato Seiko、Takahashi Satoshi、Nannya Yasuhito、Tsuru Yukari、Konuma Takaaki
  • Journal Title: Leukemia &amp; Lymphoma Volume: 65 Issue: 4 Pages: 516-520
  • DOI: 10.1080/10428194.2023.2298698
  • Peer Reviewed
• [Journal Article] Allogeneic hematopoietic cell transplantation for patients with acute myeloid leukemia not in remission (2023)
  • Author(s): Yanada M, Yamasaki S, Kondo T, Kawata T, Harada K, Uchida N, Doki N, Yoshihara S, Katayama Y, Eto T, Tanaka M, Takada S, Kawakita T, Nishida T, Ota S, Serizawa K, Onizuka M, Kanda Y, Fukuda T, Atsuta Y, Konuma T
  • Journal Title: Leukemia Volume: 38 Issue: 3 Pages: 513-520
  • DOI: 10.1038/s41375-023-02119-0
  • Peer Reviewed
• [Journal Article] Clinical implications of augmented renal clearance after unrelated single cord blood transplantation in adults (2023)
  • Author(s): Konuma Takaaki、Takano Kosuke、Monna-Oiwa Maki、Isobe Masamichi、Kato Seiko、Takahashi Satoshi、Nannya Yasuhito
  • Journal Title: International Journal of Hematology Volume: 118 Issue: 6 Pages: 718-725
  • DOI: 10.1007/s12185-023-03669-w
  • Peer Reviewed / Open Access
• [Journal Article] Single-unit unrelated cord blood transplantation versus HLA-matched sibling transplantation in adults with advanced myelodysplastic syndrome: A registry-based study from the adult MDS working group of the Japanese society for transplantation and cellular therapy. (2023)
  • Author(s): Konuma T, Itonaga H, Shimomura Y, Fujioka M, Aoki K, Uchida N, Onizuka M, Jinguji A, Tanaka M, Ueda Y, Katayama Y, Sawa M, Tanaka H, Nakamae H, Kawakita T, Maruyama Y, Takahashi S, Ishimaru F, Kanda J, Ichinohe T, Atsuta Y.
  • Journal Title: Hematological Oncology. Volume: 42 Issue: 1
  • DOI: 10.1002/hon.3217
  • Peer Reviewed / Open Access
• [Journal Article] External validation and extended application of the transplant conditioning intensity score in acute myeloid leukemia (2023)
  • Author(s): Yanada M, Shimomura Y, Mizuno S, Matsuda K, Kondo T, Doki N, Tanaka M, Fukuda T, Ara T, Uchida N, Onizuka M, Sawa M, Ozawa Y, Hiramoto N, Ota S, Kanda J, Kanda Y, Ichinohe T, Okamoto S, Atsuta Y, Konuma T
  • Journal Title: Bone Marrow Transplantation Volume: 58 Issue: 10 Pages: 1096-1103
  • DOI: 10.1038/s41409-023-02037-w
  • Peer Reviewed
• [Journal Article] Pretransplantation EASIX Score Predicts Nonrelapse and Overall Mortality of Adult Patients Undergoing Single-Unit Unrelated Cord Blood Transplantation (2023)
  • Author(s): Fujita Sumiko、Monna-Oiwa Maki、Kato Seiko、Isobe Masamichi、Takahashi Satoshi、Nannya Yasuhito、Konuma Takaaki
  • Journal Title: Transplantation and Cellular Therapy Volume: 29 Issue: 9 Pages: 580.e1-580.e8
  • DOI: 10.1016/j.jtct.2023.06.021
  • Peer Reviewed
• [Journal Article] Should a matched sibling donor still be considered the primary option for allogeneic hematopoietic cell transplantation in patients over 50 years of age with myelodysplastic syndrome? (2023)
  • Author(s): Konuma T, Itonaga H, Ishiyama K, Doki N, Uchida N, Sawa M, Katayama Y, Tanaka M, Ueda Y, Onizuka M, Miyakoshi S, Ozawa Y, Fukuda T, Matsuoka KI, Tanaka J, Kimura T, Ichinohe T, Atsuta Y.
  • Journal Title: Bone Marrow Transplantation. Volume: 58 Issue: 8 Pages: 893-906
  • DOI: 10.1038/s41409-023-01997-3
  • Peer Reviewed / Open Access
• [Journal Article] Effect of Graft-versus-Host Disease on Post-Transplantation Outcomes following Single Cord Blood Transplantation Compared with Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for Adult Acute Myeloid Leukemia (2023)
  • Author(s): Konuma Takaaki、Matsuda Kensuke、Shimomura Yoshimitsu、et al.
  • Journal Title: Transplantation and Cellular Therapy Volume: Online ahead of print Issue: 6 Pages: 365.e1-365.e11
  • DOI: 10.1016/j.jtct.2023.03.001
  • Peer Reviewed
• [Journal Article] Progress in survival following three decades of allogeneic hematopoietic cell transplantation for myelodysplastic syndrome: A real‐world registry study in Japan (2023)
  • Author(s): Konuma Takaaki、Itonaga Hidehiro、Ishiyama Ken、Hamamura Atsushi、Uchida Naoyuki、Ozawa Yukiyasu、Katayama Yuta、Sakurai Masatoshi、Ueda Yasunori、Matsuoka Ken‐ichi、Kawakita Toshiro、Eto Tetsuya、Ara Takahide、Kanda Junya、Onizuka Makoto、Fukuda Takahiro、Atsuta Yoshiko
  • Journal Title: American Journal of Hematology Volume: 98 Issue: 4
  • DOI: 10.1002/ajh.26839
  • Peer Reviewed / Open Access
• [Presentation] A recent update on cord blood transplantation in Japan (2024)
  • Author(s): Konuma T
  • Organizer: 第46回日本造血・免疫細胞療法学会
  • Invited
• [Presentation] TRUMPデータ解析から論文作成まで (2024)
  • Author(s): 小沼貴晶
  • Organizer: 第46回日本造血・免疫細胞療法学会
  • Invited
• [Presentation] 50歳以上の急性骨髄性白血病でHLA一致同胞ドナーは第一選択となりえるか？ (2024)
  • Author(s): 小沼 貴晶、山崎 聡、石山 謙、水野 昌平、林 裕美、内田 直之、土岐 典子、田中 正嗣、衛藤 徹也、鬼塚 真仁、石綿 一哉、澤 正史、田中 喬、大東 寛幸、藤原 慎一郎、松岡 賢市、太田 秀一、西田 徹也、神田 善伸、福田 隆浩、熱田 由子、仲宗根 秀樹、柳田 正光
  • Organizer: 第46回日本造血・免疫細胞療法学会
• [Presentation] 臍帯血移植及び骨髄移植後成人レシピエントにおける新型コロナウイルスワクチン及び感染に対する細胞性および液性免疫能 (2023)
  • Author(s): 小沼貴晶、濱谷恵、永井悦子、安達英輔、加藤せい子、磯部優理、高橋聡、四柳宏、南谷泰仁
  • Organizer: 第85回日本血液学会学術集会