樹状細胞・腫瘍免疫研究室

樹状細胞・腫瘍免疫研究グループは，血液・腫瘍内科の疾患，特に造血器腫瘍の病態および治療における免疫系の解析を通じて免疫メカニズムを深く理解することにより， 免疫制御による新たな治療アプローチを開発するとともに，ヒトの免疫系に関する新たな知見を得ることを目標にしています。 その方法として，免疫系において司令塔的な役割を果たしている樹状細胞（dendritic cells: DC）や腫瘍免疫エフェクターとして重要なT細胞・NK細胞にフォーカスを当てて解析を行っています。 また、CAR-T細胞療法の向上のために新たなレセプターやリガンドの開発に取り組んでいます。

　また、新たな取り組みとして急性リンパ性白血病(Acute lymphoblastic leukemia: ALL)の治療抵抗性メカニズム及び、主たるエフェクターであるT細胞の抗白血病機能の解析に取り組んでいます。ALLは近年、新しい抗体医薬やCAR-T細胞療法によって治療成績は向上しているものの、再発例が多く、その予後は不良です。血液内科医として、このような難治性ALLの克服のために、腫瘍側や免疫側のいずれかだけでなく、両方向の視野に立って、CRISPRシステムやシングルセル解析を駆使して、研究を進めています。 近年，がん免疫療法が目覚ましい発展を遂げつつあり，免疫の知識は，今後，血液・腫瘍内科の臨床をする上でも重要な素養になっていきます。免疫学に興味があり，免疫の世界を究めたいと思う方は是非当研究室の門を叩いてください！

代表的な業績

• 1)　Wintering A*, Ishiyama K*, Tamaki SJ, Tamaki CM, Fandel JY, Ji L, Wood BL, Shah NN, Yuan CM, O’Brien MM, Loh ML, Diaz-Flores E. CD22low/Bcl-2high expression identifies poor response to inotuzumab in relapsed/refractory acute lymphoblastic leukemia. Blood Adv. 7(2):251-255, 2023. *These authors contributed equally as first to this work. [PubMed]
• 2)　Ishiyama K, Arakawa-Hoyt J, Aguilar OA, Damm I, Towfighi P, Sigdel T, Tamaki S, Babdor J, Spitzer MH, Reed EF, Sarwal MM, Lanier LL; CMV Systems Immunobiology Group. Mass cytometry reveals single-cell kinetics of cytotoxic lymphocyte evolution in CMV-infected renal transplant patients. Proc Natl Acad U S A. 119(8):e2116588119, 2022. [PubMed]
• 3)　Good CR, Aznar MA, Kuramitsu S, Samareh P, Agarwal S, Donahue G, Ishiyama K, Wellhausen N, Rennels AK, Ma Y, Tian L, Guedan S, Alexander KA, Zhang Z, Rommel PC, Singh N, Glastad KM, Richardson MW, Watanabe K, Tanyi JL, O'Hara MH, Ruella M, Lacey SF, Moon EK, Schuster SJ, Albelda SM, Lanier LL, Young RM, Berger SL, June CH. An NK-like CAR T cell transition in CAR T cell dysfunction. Cell. 184(25):6081-6100, 2021. [PubMed]
• 4)　Pickering H, Sen S, Arakawa-Hoyt J, Ishiyama K, Sun Y, Parmar R, Ahn RS, Sunga G, Llamas M, Hoffmann A, Deng M, Bunnapradist S, Schaenman JM, Gjertson DW, Rossetti M, Lanier LL, Reed EF; CMV Systems Immunology Group. NK and CD8+T cell phenotypes predict onset and control of CMV viremia after kidney transplant. insight . 6(21): e153175, 2021. [PubMed]
• 5)　Ishiyama K, Kitawaki T, Otsuka Y, Takaori-Kondo A, Kadowaki N. Programmed cell death 1-expressing CD56-negative natural killer (NK) cell expansion is a hallmark of chronic NK cell activation during dasatinib treatment.Cancer Sci. 2021 Feb;112(2):523-536. [PubMed]
• 6)　Yamamoto K, Kitawaki T, Sugimoto N, Fujita H, Kawase Y, Takaori-Kondo A, Kadowaki N. Anti-inflammatory modulation of human myeloid-derived dendritic cell subsets by lenalidomide. Immunol Lett. 211:41-48, 2019. [PubMed]
• 7)　Ishiyama K, Kitawaki T, Sugimoto N, Sozu T, Anzai N, Okada M, Nohgawa M, Hatanaka K, Arima N, Ishikawa T, Tabata S, Onaka T, Oka S, Nakabo Y, Amakawa R, Matsui M, Moriguchi T, Takaori-Kondo A, Kadowaki N.  Principal component analysis uncovers cytomegalovirus-associated NK cell activation in Ph+ leukemia patients treated with dasatinib.  Leukemia. 2017; 31(1):203-212. [PubMed]
• 8)　Sato T, Kitawaki T, Fujita H, Iwata M, Iyoda T, Inaba K, Ohteki T, Hasegawa S, Kawada K, Sakai Y, Ikeuchi H, Nakase H, Niwa A, Takaori-Kondo A, Kadowaki N. Human CD1c+ Myeloid Dendritic Cells Acquire a High Level of Retinoic Acid-Producing Capacity in Response to Vitamin D3. J Immunol. 191(6): 3152-60, 2013 [PubMed]
• 9)　Fujita H, Kitawaki T, Sato T, Maeda T, Kamihira S, Takaori-Kondo A, Kadowaki N. The tyrosine kinase inhibitor dasatinib suppresses cytokine production by plasmacytoid dendritic cells by targeting endosomal transport of CpG DNA. Eur J Immunol. 43(1):93-103, 2013. [PubMed]
• 10)　Kitawaki T, Kadowaki N, Fukunaga K, Kasai Y, Maekawa T, Ohmori K, Kondo T, Maekawa R, Takahara M, Nieda M, Kuzushima K, Ishikawa T, Uchiyama T. A phase I/IIa clinical trial of immunotherapy for elderly patients with acute myeloid leukemia using dendritic cells co-pulsed with WT1 peptide and zoledronate. Br J Haematol 153: 796-799, 2011. [PubMed]
• 11)　Kitawaki T, Kadowaki N, Fukunaga K, Kasai Y, Maekawa T, Ohmori K, Itoh T, Shimizu A, Kuzushima K, Kondo T, Ishikawa T, Uchiyama T. Cross-priming of CD8+ T cells in vivo by dendritic cells pulsed with autologous apoptotic leukemic cells in immunotherapy for elderly patients with acute myeloid leukemia. Exp Hematol 39: 424-433, 2011. [PubMed]
• 12)　Hirai M, Kadowaki N, Kitawaki T, Fujita H, Takaori-Kondo A, Fukui R, Miyake K, Maeda T, Kamihira S, Miyachi Y, Uchiyama T. Bortezomib suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular trafficking of Toll-like receptors and endoplasmic reticulum homeostasis. Blood117: 500-509, 2011. [PubMed]
• 13)　Arimoto-Miyamoto K, Kadowaki N, Kitawaki T, Iwata S, Morimoto C, Uchiyama T. Optimal stimulation for CD70 induction on human monocyte-derived dendritic cells and the importance of CD70 in naive CD4+ T cell differentiation. Immunology 130: 137-149, 2010. [PubMed]
• 14)　北脇年雄、門脇則光：がん免疫療法—実用化へのチャレンジ—、第5章 樹状細胞ワクチン、シーエムシー出版、2010. [Amazon]
• 15)　Kadowaki N. The divergence and interplay between pDC and mDC in humans. Front Biosci 14:808-817, 2009. [PubMed]
• 16)　Hashimoto-Okada M, Kitawaki T, Kadowaki N, Iwata S, Morimoto C, Hori T, Uchiyama T. The CD70-CD27 interaction during the stimulation with dendritic cells promotes na?ve CD4+ T cells to develop into T cells producing a broad array of immunostimulatory cytokines in humans. Int Immunol 21: 891-904, 2009. [PubMed]
• 17)　Kitawaki T, Kadowaki N, Kondo T, Ishikawa T, Ichinohe T, Teramukai S, Fukushima M, Kasai Y, Maekawa T, Uchiyama T. Potential of dendritic cell immunotherapy for relapse after allogeneic hematopoietic stem cell transplantation, shown by WT1 peptide- and keyhole limpet hemocyanin-pulsed, donor-derived dendritic cell vaccine for acute myeloid leukemia. Am J Hematol 83: 315-317, 2008.[PubMed]
• 18)　Kawamura K, Kadowaki N, Kitawaki T, and Uchiyama T. Virus-stimulated plasmacytoid dendritic cells induce CD4+ cytotoxic regulatory T cells. Blood 107: 1031-1038, 2006. [PubMed]
• 19)　Kawamura K, Kadowaki N, Suzuki R, Udagawa S, Kasaoka S, Utoguchi N, Kitawaki T, Sigimoto N, Okada N, Maruyama K, and Uchiyama T. Dendritic cells that endocytosed antigen-containing IgG-liposomes elicit effective anti-tumor immunity. J Immunother 29:165-174, 2006. [PubMed]