Search of the new biomarkers reflecting lymph node macrophage function and its application to molecular pathology

• Project/Area Number: 16K15248
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Human pathology
• Research Institution: Kumamoto University
• Principal Investigator: Takeya Motohiro 熊本大学, 事務局, 理事 (90155052)
• Co-Investigator(Kenkyū-buntansha): 哈 斯塔 (Horlad Hasita) 熊本大学, 大学院生命科学研究部(医), 研究員 (00644840) ; 大西 紘二 熊本大学, 大学院生命科学研究部(医), 助教 (40613378)
• Research Collaborator: FUJIWARA Yukio ; KOMOHARA Yoshihiro ; ASANO Kenichi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: CD169 / リンパ洞マクロファージ / ヒト癌組織 / 抗腫瘍免疫 / CCL8 / 膀胱癌 / 食道癌 / 子宮内膜癌 / バイオマーカー / 天然化合物 / 膵癌 / CXCL10 / 乳癌 / 大腸癌

Outline of Final Research Achievements

In the analysis of the patients of endometrial cancer, pancreatic cancer, bladder cancer and esophagus cancer, positive correlation between CD169-positive rate of lymph node sinus macrophages and overall or cancer-specific survival rate was observed. A concomitant correlation with the density of the intratumoral CD8-positive T lymphocytes was also noted in most cancer cases. We identified that indoleamine 2,3-dioxygenase 1 shows similar expression pattern with CD169 in human macrophages, however, their staining pattern in lymph nodes differed indicating functional association between these molecules may not exist. In colon cancer patients, a possible correlation of blood level of CCL8 and CD169-positive rate of sinus macrophages was indicated, however, the significant difference was not proved.

Academic Significance and Societal Importance of the Research Achievements

多くの癌腫症例において、所属リンパ節洞ＭφにおけるCD169発現は、癌患者のCD8陽性Ｔリンパ球を介した抗腫瘍免疫の活性化の程度と相関し、患者予後を予測する分子マーカーとして有用であると考えられた。また、洞ＭφにおけるCD169の発現増強は抗腫瘍免疫の賦活化に関わる可能性が示唆され、洞Ｍφの活性化は癌治療のターゲットの一つとなり得ることが示唆された。一方、リンパ洞ＭφにおけるCD169分子の機能については未解明の部分が多く、その機能を反映する血清マーカーについても有用な分子を同定することが出来ず、今後の課題と考えられた。

Research Products

• [Journal Article] High CD169 expression in lymph node macrophages predicts a favorable clinical course in patients with esophageal cancer. (2018)
  • Author(s): Takeya H, Shiota T, Yagi T, Ohnishi K, Baba Y, Miyasato Y, Kiyozumi Y, Yoshida N, Takeya M, Baba H, Komohara Y.
  • Journal Title: Pathology international Volume: 68 Issue: 12 Pages: 685-693
  • DOI: 10.1111/pin.12736
  • Peer Reviewed / Open Access
• [Journal Article] CD169-positive sinus macrophages in the lymph nodes determine bladder cancer prognosis (2018)
  • Author(s): Asano Touko、Ohnishi Koji、Shiota Takuya、Motoshima Takanobu、Sugiyama Yutaka、Yatsuda Junji、Kamba Tomomi、Ishizaka Kazuhiro、Komohara Yoshihiro
  • Journal Title: Cancer Science Volume: 109 Issue: 5 Pages: 1723-1730
  • DOI: 10.1111/cas.13565
  • Peer Reviewed / Open Access
• [Journal Article] CD163 is required for protumoral activation of macrophages in human and murine sarcoma. (2018)
  • Author(s): Shiraishi D, Fujiwara Y, Horlad H, Saito Y, Iriki T, Tsuboki J, Cheng P, Nakagata N, Mizuta H, Bekki H, Nakashima Y, Oda Y, Takeya M, Komohara Y.
  • Journal Title: Cancer Res Volume: in press Issue: 12 Pages: 3255-3266
  • DOI: 10.1158/0008-5472.can-17-2011
  • Peer Reviewed
• [Journal Article] The expression of PD-1 ligands and IDO1 by macrophage/microglia in primary central nervous system lymphoma (2018)
  • Author(s): Miyasato Yuko、Takashima Yasuo、Takeya Hiroto、Yano Hiromu、Hayano Azusa、Nakagawa Takenobu、Makino Keishi、Takeya Motohiro、Yamanaka Ryuya、Komohara Yoshihiro
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 58 Issue: 2 Pages: 95-101
  • DOI: 10.3960/jslrt.18001
  • NAID: 130007403913
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed / Open Access
• [Journal Article] Positive correlation between the density of macrophages and T-cells in undifferentiated sarcoma (2018)
  • Author(s): Komohara Yoshihiro、Takeya Hiroto、Wakigami Nanako、Kusada Natsuki、Bekki Hirofumi、Ishihara Shin、Takeya Motohiro、Nakashima Yasuharu、Oda Yoshinao
  • Journal Title: Medical Molecular Morphology Volume: 52 Issue: 1 Pages: 44-51
  • DOI: 10.1007/s00795-018-0201-3
  • Peer Reviewed
• [Journal Article] Differential roles of Rad18 and Chk2 in genome maintenance and skin carcinogenesis following UV exposure. (2018)
  • Author(s): Tanoue, Y., Toyoda, T., Sun, J, Mustofa, M.K., Tateishi, C., Endo, S., Motoyama, N., Araki, K., Wu, D., Okuno, Y., Tsukamoto, T., Takeya, M., Ihn, H., Vaziri, C., Tateishi, S.
  • Journal Title: J. Invest. Dermatol. Volume: 138 Issue: 12 Pages: 2550-2557
  • DOI: 10.1016/j.jid.2018.05.015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Oligodendrocyte Progenitor Cells and Macrophages/Microglia Produce Glioma Stem Cell Niches at the Tumor Border. (2018)
  • Author(s): Hide T, Komohara Y, Miyasato Y, Nakamura H, Makino K, Takeya M, Kuratsu JI, Mukasa A, Yano S.
  • Journal Title: EBioMedicine. Volume: 30 Pages: 94-104
  • DOI: 10.1016/j.ebiom.2018.02.024
  • Peer Reviewed / Open Access
• [Journal Article] Natural compounds that regulate lymph node sinus macrophages: Inducing an anti-tumor effect by regulating macrophage activation (2018)
  • Author(s): Fujiwara Y, Saito Y, Shiota T, Cheng P, Ikeda T, Ohnishi K, Takeya M, Komohara Y
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 58 Issue: 1 Pages: 17-23
  • DOI: 10.3960/jslrt.17032
  • NAID: 130006512988
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed / Open Access
• [Journal Article] Phenotypical change of tumor-associated macrophages in metastatic lesions of clear cell renal cell carcinoma (2018)
  • Author(s): Motoshima Takanobu、Miura Yuji、Wakigami Nanako、Kusada Natsuki、Takano Toshimi、Inoshita Naoko、Okaneya Toshikazu、Sugiyama Yutaka、Kamba Tomomi、Takeya Motohiro、Komohara Yoshihiro
  • Journal Title: Medical Molecular Morphology Volume: 51 Issue: 1 Pages: 57-63
  • DOI: 10.1007/s00795-017-0174-7
  • Peer Reviewed
• [Journal Article] CD163-positive cancer cells are potentially associated with high malignant potential in clear cell renal cell carcinoma (2018)
  • Author(s): Ma Chaoya、Horlad Hasita、Ohnishi Koji、Nakagawa Takenobu、Yamada Sohsuke、Kitada Shohei、Motoshima Takanobu、Kamba Tomomi、Nakayama Toshiyuki、Fujimoto Naohiro、Takeya Motohiro、Komohara Yoshihiro
  • Journal Title: Medical Molecular Morphology Volume: 51 Issue: 1 Pages: 13-20
  • DOI: 10.1007/s00795-017-0165-8
  • Peer Reviewed
• [Journal Article] がん免疫(第7回) がん免疫におけるマクロファージの意義とその制御 (2018)
  • Author(s): 菰原義弘、大西紘二、藤原章雄、竹屋元裕
  • Journal Title: 炎症と免疫 Volume: 26 Pages: 56-61
• [Journal Article] Possible functions of CD169-positive sinus macrophages in lymph nodes in anti-tumor immune responses. (2017)
  • Author(s): Komohara Y, Ohnishi K, Takeya M.
  • Journal Title: Cancer Sci Volume: 108 Issue: 3 Pages: 290-295
  • DOI: 10.1111/cas.13137
  • Peer Reviewed / Open Access
• [Journal Article] PD-L1 expression in papillary renal cell carcinoma (2017)
  • Author(s): Takanobu Motoshima, Yoshihiro KomoharaEmail author, Chaoya Ma, Arni Kusuma Dewi, Hirotsugu Noguchi, Sohsuke Yamada, Toshiyuki Nakayama, Shohei Kitada, Yoshiaki Kawano, Wataru Takahashi, Masaaki Sugimoto, Motohiro Takeya, Naohiro Fujimoto, Yoshinao Oda and Masatoshi Eto
  • Journal Title: BMC Urology Volume: 17 Issue: 1 Pages: 8-8
  • DOI: 10.1186/s12894-016-0195-x
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Recent advances in research regarding to natural compounds that target pro-tumor macrophages. (2017)
  • Author(s): Komohara Y, Fujiwara Y, Ohnishi K, Horlad H, Saito Y, Takeya M.
  • Journal Title: Macrophage Volume: 4
  • DOI: 10.14800/macrophage.1507
  • Peer Reviewed / Open Access
• [Journal Article] The cell-cell interaction between tumor-associated macrophages and small cell lung cancer cells is involved in tumor progression via STAT3 activation (2017)
  • Author(s): Iriki Toyohisa、Ohnishi Koji、Fujiwara Yukio、Horlad Hasita、Saito Yoichi、Pan Cheng、Ikeda Koei、Mori Takeshi、Suzuki Makoto、Ichiyasu Hidenori、Kohrogi Hirotsugu、Takeya Motohiro、Komohara Yoshihiro
  • Journal Title: Lung Cancer Volume: 106 Pages: 22-32
  • DOI: 10.1016/j.lungcan.2017.01.003
  • Peer Reviewed
• [Journal Article] Cell adhesion molecule-1 (CADM1) expressed on adult T-cell leukemia/lymphoma cells is not involved in the interaction with macrophages. (2017)
  • Author(s): Komohara Y, Ma C, Yano H, Pan C, Horlad H, Saito Y, Ohnishi K, Fujiwara Y, Okuno Y, Nosaka K, Shimosaki S, Morishita K, Matsuoka M, Wakayama T, Takeya M
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 57 Issue: 1 Pages: 15-20
  • DOI: 10.3960/jslrt.17003
  • NAID: 130005709559
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed / Open Access
• [Journal Article] Stat3 inhibitor abrogates the expression of PD-1 ligands on lymphoma cell lines (2017)
  • Author(s): Ma C, Horlad H, Pan C, Yano H, Ohnishi K, Fujiwara Y, Matsuoka M, Lee A, Niidome T, Yamanaka R, Takeya M, Komohara Y
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 57 Issue: 1 Pages: 21-25
  • DOI: 10.3960/jslrt.17006
  • NAID: 130005709510
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic significance of CD169-positive lymph node sinus macrophages in patients with endometrial carcinoma. (2016)
  • Author(s): Ohnishi K, Yamaguchi M, Erdenebaatar C, Saito F, Tashiro H, Katabuchi H, Takeya M, Komohara Y.
  • Journal Title: Cancer Sci Volume: - Issue: 6 Pages: 846-852
  • DOI: 10.1111/cas.12929
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of tumor-associated macrophages in human malignancies: friend or foe? (2016)
  • Author(s): Takeya M, Komohara Y.
  • Journal Title: Pathol Int Volume: 66 Issue: 9 Pages: 491-505
  • DOI: 10.1111/pin.12440
  • Peer Reviewed
• [Journal Article] An IL-27/Stat3 axis induces expression of programmed cell death 1 ligands (PD-L1/2) on infiltrating macrophages in lymphoma. (2016)
  • Author(s): Horlad H, Ma C, Yano H, Pan C, Ohnishi K, Fujiwara Y, Endo S, Kikukawa Y, Okuno Y, Matsuoka M, Takeya M, Komohara Y.
  • Journal Title: Cancer Sci. Volume: 107 Issue: 11 Pages: 1696-1704
  • DOI: 10.1111/cas.13065
  • NAID: 120006223644
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Clinical Significance of CD169-Positive Lymph Node Macrophage in Patients with Breast Cancer. (2016)
  • Author(s): Shiota T, Miyasato Y, Ohnishi K, Yamamoto-Ibusuki M, Yamamoto Y, Iwase H, Takeya M, Komohara Y.
  • Journal Title: PLoS One Volume: 11 Issue: 11 Pages: e0166680-e0166680
  • DOI: 10.1371/journal.pone.0166680
  • Peer Reviewed / Open Access
• [Journal Article] Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy. (2015)
  • Author(s): Yoshihiro Komohara, Yukio Fujiwara, Koji Ohnishi, Motohiro Takeya
  • Journal Title: Advanced drug delivery reviews Volume: 24 Pages: 180-185
  • DOI: 10.1016/j.addr.2015.11.009
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 環状硫黄化合物による腫瘍関連マクロファージをターゲットとしたがん治療への応用 (2019)
  • Author(s): 藤原章雄、大西紘二、菰原義弘
  • Organizer: 日本薬学会 第139回年会
• [Presentation] マクロファージと老化 ― 加齢関連疾患におけるマクロファージの役割 シンポジウム (2018)
  • Author(s): 竹屋元裕、菰原義弘、藤原章雄
  • Organizer: 第18回 日本抗加齢医学会総会
  • Invited
• [Presentation] The significance of lymph node macrophages in the induction of anti-tumor immune response in human malignant tumors (2018)
  • Author(s): Yoshihiro Komohara, Yoichi Saito, Takuya Shiota, Hiroto Takeya, Yukio Fujiwara, Koji Ohnishi
  • Organizer: 第45回 内藤コンファレンス
• [Presentation] マクロファージCD163の肉腫進展における機能解析 (2018)
  • Author(s): 藤原章雄、白石大偉輔、西東洋一、潘 程、小田義直、竹屋元裕、菰原義弘
  • Organizer: 第58回 日本リンパ網内系学会
• [Presentation] 腫瘍随伴マクロファージ（TAM）の機能とその由来の多様性 (2018)
  • Author(s): 竹屋元裕、菰原義弘、藤原章雄、大西紘二
  • Organizer: 第28回 樹状細胞研究会
• [Presentation] 食道癌におけるCD169陽性リンパ節洞マクロファージとがん免疫の関連性 (2018)
  • Author(s): 竹屋裕斗、塩田拓也、大西紘二、菰原義弘
  • Organizer: 第22回 日本がん免疫学会総会
• [Presentation] がん免疫におけるリンパ節マクロファージの重要性 (2018)
  • Author(s): 菰原義弘、藤原章雄、大西紘二、西東洋一
  • Organizer: 第77回 日本癌学会学術総会
• [Presentation] 腫瘍境界部のグリオーマ細胞は特殊な微小環境を利用し治療抵抗性を獲得する (2018)
  • Author(s): 秀拓一郎、菰原義弘、宮里祐子、中村英夫、牧野敬史、竹屋元裕、倉津純一、武笠晃丈、矢野茂敏
  • Organizer: 第77回 日本癌学会学術総会
• [Presentation] Orosomucoid is indirectly involved in tumor development via macrophages. (2018)
  • Author(s): Yukio Fujiwara, Koji Ohnishi, Yoshihiro Komohara, Cheng Pan
  • Organizer: AACR-JCA Joint Conference
  • Int'l Joint Research
• [Presentation] Targeting cholesterol efflux is a promising approach for anti-lymphoma therapy. (2018)
  • Author(s): Cheng Pan, Hasita Horlad, Yukio Fujiwara, Daisuke Niino, Yutaka Okuno, Masao Matsuoka, Motohiro Takeya, Yoshihiro Komohara.
  • Organizer: The 14th Japanese-Korean Lymphoreticular Workshop 2018
• [Presentation] がんのPD-L1発現多様性とリンパ節洞マクロファージのCD169発現に着目したコンパニオン診断の可能性. (2018)
  • Author(s): 大西紘二
  • Organizer: Kyusyu Cancer Immunology Forum
• [Presentation] Pivotal of lymph node macrophages in the induction of anti-tumor immune response. (Abstract only) (2017)
  • Author(s): Yoshihiro Komohara, Koji Ohnishi, Motohiro Takeya.
  • Organizer: Keystone Symposia, Cancer Immunology and Immunotherapy: Taking a place in mainstream oncology
• [Presentation] リンパ節マクロファージに注目した、大腸癌に対する抗腫瘍免疫能評価のためのバイオマーカーの探索 (2017)
  • Author(s): 大西紘二、菰原義弘、塩田拓也、西東洋一、竹屋元裕
  • Organizer: 第106回 日本病理学会総会
• [Presentation] 腫瘍随伴マクロファージにより活性化される小細胞肺癌におけるSTAT3の治療標的としての可能性 (2017)
  • Author(s): 入來豊久、大西紘二、藤原章雄、潘 程、興梠博次、菰原義弘、竹屋元裕
  • Organizer: 第106回 日本病理学会総会
• [Presentation] 膵癌患者におけるCD169陽性リンパ節マクロファージの臨床的意義 (2017)
  • Author(s): 塩田拓也、大西紘二、長峯理子、福田精二、西東洋一、竹屋元裕、菰原義弘
  • Organizer: 第106回 日本病理学会総会
• [Presentation] タマネギ成分のマクロファージ活性化制御を介した抗腫瘍作用と新たな抗ガン剤のリード化合物としての可能性 (2017)
  • Author(s): 藤原章雄、坪木純子、野原稔弘、中川雄伸、菰原義弘、竹屋元裕
  • Organizer: 第106回 日本病理学会総会
• [Presentation] 炎症性マクロファージの新たなマーカー探索 (2017)
  • Author(s): 藤原章雄、菰原義弘、大西紘二、宮川育子、中川雄伸、竹屋元裕
  • Organizer: 第70回 日本酸化ストレス学会学術集会
• [Presentation] INFsによるがんのPD-L1発現多様性とリンパ節洞マクロファージのCD169に着目した抗PD-(L)1抗体薬新規コンパニオン診断の可能性 (2017)
  • Author(s): 西東洋一、藤原章雄、大西紘二、菰原義弘、竹屋元裕
  • Organizer: 第21回 日本がん免疫学会総会
• [Presentation] Investigation of new serum biomarkers released by lymph node macrophages for assessment of anti-tumor immunity in patients with colorectal cancer. (2017)
  • Author(s): Koji Ohnishi.
  • Organizer: Kumamoto University Advance Research Project A "International Research Center for Cancer and Metabolism"
  • Place of Presentation: Kumamoto University, Kumamoto
  • Int'l Joint Research
• [Presentation] PD-L1/2 expressions in tumor associated macrophages are dependent on IL-27/Stat3 signal. (2017)
  • Author(s): Hsita Horlad.
  • Organizer: Kumamoto University Advance Research Project A "International Research Center for Cancer and Metabolism"
  • Place of Presentation: Kumamoto University, Kumamoto
  • Int'l Joint Research
• [Presentation] 乳癌患者におけるリンパ節CD169陽性マクロファージの臨床病理学的研究. (2016)
  • Author(s): 塩田拓也、宮里祐子、大西紘二、指宿睦子、岩瀬弘敬、竹屋元裕、菰原義弘
  • Organizer: 第75回 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜、横浜
  • Year and Date: 2016-10-06
• [Presentation] ヒト悪性腫瘍におけるマクロファージの役割ーがん免疫との接点 (2016)
  • Author(s): 菰原義弘、大西紘二、藤原章雄、竹屋元裕.
  • Organizer: 第44回 日本臨床免疫学会総会
  • Place of Presentation: 京王プラザホテル、東京
  • Year and Date: 2016-09-08
  • Invited
• [Presentation] がん患者の抗腫瘍免疫におけるCD169陽性リンパ節洞マクロファージの重要性 (2016)
  • Author(s): 大西紘二、菰原義弘、西東洋一、藤原章雄、竹屋元裕.
  • Organizer: 第56回 日本リンパ網内系学会総会
  • Place of Presentation: ホテル日航熊本、熊本
  • Year and Date: 2016-09-01
• [Presentation] The clinical relevance and prognostic significance of CD169+ lymph node macrophages in human malignant tumors. (2016)
  • Author(s): Koji Ohnishi, Yoichi Saito, Takuya Shiota, Hasita Horlad, Yukio Fujiwara, Motohiro Takeya, Yoshihiro Komohara.
  • Organizer: The 24th International Symposium on Molecular Cell Biology of Macrophages
  • Place of Presentation: Sola City Conference Center, Tokyo
  • Year and Date: 2016-06-04
  • Int'l Joint Research
• [Presentation] 乳癌患者におけるリンパ節CD169陽性マクロファージの臨床病理学的研究. (2016)
  • Author(s): 塩田拓也、宮里祐子、大西紘二、菰原義弘、指宿睦子、岩瀬弘敬、竹屋元裕.
  • Organizer: 第26回 日本樹状細胞研究会
  • Place of Presentation: ホテル日航熊本、熊本
• [Presentation] 悪性腫瘍患者におけるCD169陽性リンパ節洞マクロファージの臨床的意義 (2016)
  • Author(s): 大西紘二、西東洋一、塩田拓也、ハスタ ホルラド、藤原章雄、竹屋元裕、菰原義弘
  • Organizer: 第62回 日本病理学会総会
  • Place of Presentation: 金沢市文化ホール、金沢
• [Remarks] 熊本大学大学院生命科学研究部 細胞病理学講座
  • URL: http://srv02.medic.kumamoto-u.ac.jp/dept/patho2/patho2.html
• [Remarks] 熊本大学 大学院生命科学研究部 細胞病理学分野
  • URL: http://srv02.medic.kumamoto-u.ac.jp/dept/patho2/patho2.html