Development of HCC treatment by analyzing the induction of MDSC, TAM and Tregs

• Project/Area Number: 25460970
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tohoku University
• Principal Investigator: Kondo Yasuteru 東北大学, 医学(系)研究科(研究院), 非常勤講師 (70455822)
• Co-Investigator(Kenkyū-buntansha): KOGURE Takayuki 東北大学, 大学病院, 助教 (70400330) ; KAKAZU Eiji 東北大学, 高度教養教育・学生支援機構, 助教 (20509377)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: HCC / MDSCs / PD-L1 / Tregs / HBV / HCV / 肝細胞癌 / 免疫細胞 / 免疫抑制細胞 / PS-L1

Outline of Final Research Achievements

We quantified PD-L1+ MDSCs in various conditions of HCC patients by using multi-color flow cytometry analysis. PBMCs from HCC patients contained significantly higher percentages of PD-L1+MDSCs in comparison to those from healthy subjects (p < 0.001). After we cocultivated PBMCs and several liver cancer cell lines in a transwell coculture system, the percentages of PD-L1+MDSCs were significantly increased compared with control (p < 0.05).Peripheral blood from HCC patients had significantly higher percentages of PD-L1+MDSCs in comparison to those of healthy subjects, and the percentages of PD-L1+MDSCs were reduced by HCC treatment, suggesting that we might use PD-L1+MDSCs as a new biomarker of HCC.

Research Products

• [Journal Article] Shifting hepatitis B virus genotypes of acute hepatitis B patients in northeast Japan (2016)
  • Author(s): Inoue J, Kondo Y, Umetsu T, Yamamoto T, Miura M, Mano Y, Kobayashi T, Obara N, Niitsuma H, Kogure T, Nakagome Y, Kimura O, Iwata T, Morosawa T, Fujisaka Y, Shimosegawa T
  • Journal Title: J Med Virol Volume: 88 Issue: 1 Pages: 69-78
  • DOI: 10.1002/jmv.24309
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Significant biomarkers for the management of HCC (2015)
  • Author(s): Kondo Y, Kimura O, Shimosegawa T
  • Journal Title: Clinical Journal of Gastroenterology Volume: Jun;8(3) Issue: 3 Pages: 109-15
  • DOI: 10.1007/s12328-015-0568-9
  • Peer Reviewed
• [Journal Article] Differential expression of CX3CL1 in HBV-replicating hepatoma cells could affect the migration-activity of CX3CR1+ immune cells (2015)
  • Author(s): Kondo Y, Kimura O, Tanaka Y, Ninomiya M, Kogure T, Inoue J, Sugiyama M, Iwata T, Morosawa T, Fujisaka Y, Shimosegawa T
  • Journal Title: J Virol. Volume: Jul 15;89(14) Issue: 14 Pages: 7016-27
  • DOI: 10.1128/jvi.00716-15
  • Peer Reviewed
• [Journal Article] Monitoring Serum Levels of Sorafenib and Its <i>N</i>-Oxide Is Essential for Long-Term Sorafenib Treatment of Patients with Hepatocellular Carcinoma (2015)
  • Author(s): Miki Shimada, Hoshimi Okawa, Yasuteru Kondo, Takahiro Maejima, Yuta Kataoka, Kanehiko Hisamichi, Masamitsu Maekawa, Masaki Matsuura, Yuko Jin, Masaru Mori, Hiroyuki Suzuki, Tooru Shimosegawa, Nariyasu Mano.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 237 Issue: 3 Pages: 173-182
  • DOI: 10.1620/tjem.237.173
  • NAID: 130005102859
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Radiation Therapy Is a Reasonable Option for Improving the Prognosis in Hepatocellular Carcinoma (2015)
  • Author(s): Kondo Y, Kimura O, Kogure T, Ninomiya M, Umezawa R, Sugawara T, Matsushita H, Jingu K, Nakagome Y, Iwta T, Morsawa T, Fujisaka Y, Iwasaki T, Shimosegawa T
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 237 Issue: 4 Pages: 249-257
  • DOI: 10.1620/tjem.237.249
  • NAID: 130005108584
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed
• [Journal Article] Radiation therapy has been shown to be adaptable for various stages of hepatocellular carcinoma (2015)
  • Author(s): Kondo Y, Kimura O and Shimosegawa T
  • Journal Title: World J Gastroenterol. Volume: 21(1) Issue: 1 Pages: 94-101
  • DOI: 10.3748/wjg.v21.i1.94
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Significant roles of regulatory T cells and myeloid derived suppressor cells in hepatitis B virus persistent infection and hepatitis B virus-related HCCs. (2015)
  • Author(s): Kondo Y and Shimosegawa T.
  • Journal Title: Int J Mol Sci. Volume: 16(2) Issue: 2 Pages: 3307-3322
  • DOI: 10.3390/ijms16023307
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Expression of EpCAM Increases in the Hepatitis B Related and the Treatment-Resistant Hepatocellular Carcinoma. (2014)
  • Author(s): Kimura O, Kondo Y, Kogure T, Kakazu E, Ninomiya M, Iwata T, Morosawa T, Shimosegawa T.
  • Journal Title: BioMed Research International Volume: 2014 Pages: 172913-172913
  • DOI: 10.1155/2014/172913
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] HPLC-UV method for determination of sorafenib and sorafenib N-oxide in human serum (2014)
  • Author(s): Shimada M, Okawa H, Maejima T, Yanagi T, Hisamichi K, Matsuura M, Akasaka K, Tsuchiya M, Kondo Y, Shimosegawa T, Mori M, Maekawa M, Suzuki H, Mano N.
  • Journal Title: Tohoku J Exp Med. Volume: 233(2) Pages: 103-12
  • Peer Reviewed / Open Access
• [Journal Article] HCV infection enhances Th17 commitment, which could affect the pathogenesis of autoimmune diseases (2014)
  • Author(s): Kondo Y, Ninomiya M, Kimura O, Machida K, Funayama R, Nagashima T, Kobayashi K, Kakazu E, Kato T, Nakayama K, Lai MM, Shimosegawa T.
  • Journal Title: PLoS One Volume: 9(6) Issue: 6 Pages: e98521-e98521
  • DOI: 10.1371/journal.pone.0098521
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The expression level of Myeloid differentiation factor 88 might be a significant biomarker for the prognosis of HCC patients (2014)
  • Author(s): Kondo Y, and Shimosegawa T.
  • Journal Title: Translational Gastrointestinal Cancer Volume: 3(2)
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of microRNA-29a in epigenetic regulation of transforming growth factor-β-induced epithelial-mesenchymal transition in hepatocellular carcinoma (2014)
  • Author(s): Kogure T, Kondo Y, Kakazu E, Ninomiya M, Kimura O, Shimosegawa T.
  • Journal Title: Hepatol Res. Volume: 2014 Issue: 8 Pages: 907-919
  • DOI: 10.1111/hepr.12188
  • Peer Reviewed
• [Journal Article] Shimosegawa T . Sequential analysis of amino acid substitutions with hepatitis B virus in association with nucleoside/nucleotide analog treatment detected by deep sequencing (2014)
  • Author(s): Ninomiya M, Kondo Y, Niihori T, Nagashima T, Kogure T, Kakazu E, Kimura O, Aoki Y, Matsubara Y
  • Journal Title: Hepatol Res Volume: 44(6) Issue: 6 Pages: 678-684
  • DOI: 10.1111/hepr.12168
  • Peer Reviewed
• [Journal Article] 1(OH) vitamin D3 supplementation improves the sensitivity of the immune-response during Peg-IFN/RBV therapy in chronic hepatitis C patients-case controlled trial (2013)
  • Author(s): Kondo Y, Kato T, Kimura O, Iwata T, Ninomiya M, Kakazu E, Miura M, Akahane T, Miyazaki Y, Kobayashi T, Ishii M, Kisara N, Sasaki K, Nakayama H, Igarashi T, Obara N, Ueno Y, Morosawa T, Shimosegawa T.
  • Journal Title: PLoS One Volume: May 23;8(5):e63672. Issue: 5 Pages: e63672-e63672
  • DOI: 10.1371/journal.pone.0063672
  • Peer Reviewed
• [Journal Article] Distinct MicroRNAs Expression Profile in Primary Biliary Cirrhosis and Evaluation of miR 505-3p and miR197-3p as Novel Biomarkers (2013)
  • Author(s): Ninomiya, M., Kondo, Y., Funayama, R., Nagashima, T., Kogure, T., Kakazu, E., Kimura, O., Ueno, Y., Nakayama, K., Shimosegawa, T.
  • Journal Title: PloS one Volume: 8 Issue: 6 Pages: e66086-e66086
  • DOI: 10.1371/journal.pone.0066086
  • Peer Reviewed
• [Journal Article] The effect of branched chain amino acid formulation on keeping the serum albumin level in the course of hepatocellular carcinoma recurrence. (2013)
  • Author(s): Kakazu E, Kondo Y, Kogure T, Ninomiya M, Kimura O, Iwata T, Morosawa T, Iwasaki T, Shimosegawa T.
  • Journal Title: Tohoku J Exp Med. Volume: 230(4) Pages: 191-196
  • Peer Reviewed
• [Journal Article] An imbalance of plasma amino acids in patients with cirrhosis disturbs the tricarboxylic acid cycle of dendritic cell. (2013)
  • Author(s): Kakazu E, Kondo Y, Kogure T, Ninomoiya M, Kimura O, Shimosegawa T
  • Journal Title: Sci Rep. Volume: 2013 Dec 10;3:3459. Issue: 1 Pages: 3459-3459
  • DOI: 10.1038/srep03459
  • Peer Reviewed
• [Journal Article] The direct effects of hepatitis C virus on the lymphoid cells (2013)
  • Author(s): Kondo Y and Shimosegawa T.
  • Journal Title: World Journal of Gastroenterology Volume: Nov 28;19(44) Pages: 7889-7895
  • Peer Reviewed
• [Presentation] The expression of Immune-miRs could contribute to the immunopathogenesis of HCV and be modified by 1(OH) vitamin D3 supplementation (2015)
  • Author(s): Yasuteru Kondo
  • Organizer: AASLD Annual Meeting
  • Place of Presentation: 米国 (サンフランシスコ)
  • Year and Date: 2015-11-13
• [Presentation] 1(OH)VitD3 supplementation could enhance Th1 immune response during Interferon-free treatment for Chronic hepatitis C patients (2015)
  • Author(s): Yasuteru Kondo
  • Organizer: American college of Gastroenterology Annual Meeting
  • Place of Presentation: 米国 (ハワイ)
  • Year and Date: 2015-10-16
• [Presentation] HBV特異的に発現が変化するmiRNAの網羅的解析 (2015)
  • Author(s): 近藤泰輝
  • Organizer: JDDW2015
  • Place of Presentation: 東京、グランドプリンスホテル新高輪
  • Year and Date: 2015-10-08
• [Presentation] インターフェロンフリー・1(OH)VitD3併用治療とインターフェロン併用・1(OH)VitD3併用治療の免疫反応比較 (2015)
  • Author(s): 近藤泰輝
  • Organizer: JDDW2015
  • Place of Presentation: 東京、グランドプリンスホテル新高輪
  • Year and Date: 2015-10-08
• [Presentation] Differential expression of soluble factors might affect the immunopathogenesis of HBV infection (2015)
  • Author(s): Yasuteru Kondo
  • Organizer: HBV international meeting
  • Place of Presentation: ドイツ（バートナウハイム)
  • Year and Date: 2015-10-04
• [Presentation] 単球細胞におけるmiR146b-5p発現低下は慢性C型肝炎の免疫病態に影響を与える (2015)
  • Author(s): 近藤泰輝
  • Organizer: 第51回 日本肝臓学会総会
  • Place of Presentation: 熊本市、ホテル日航熊本
  • Year and Date: 2015-05-21
• [Presentation] インターフェロンフリー治療とVitamin D併用治療を行った際の免疫解析 (2015)
  • Author(s): 近藤泰輝
  • Organizer: 第51回 日本肝臓学会総会
  • Place of Presentation: 熊本市、ホテル日航熊本
  • Year and Date: 2015-05-21
• [Presentation] 免疫調整作用を有するVitamin D 併用治療の解析 (2015)
  • Author(s): 近藤泰輝
  • Organizer: 第101回 日本消化器病学会総会
  • Place of Presentation: 仙台市、仙台国際センター
  • Year and Date: 2015-04-23
• [Presentation] HBV持続感染における細胞性免疫反応抑制のメカニズム解析とETV-IFN治療効果予測 (2015)
  • Author(s): 近藤泰輝
  • Organizer: 第101回 日本消化器病学会総会
  • Place of Presentation: 仙台市、仙台国際センター
  • Year and Date: 2015-04-23
• [Presentation] HBVジェノタイプ間における免疫細胞動態の差異が生じるメカニズム (2015)
  • Author(s): 近藤泰輝
  • Organizer: 第101回 日本消化器病学会総会
  • Place of Presentation: 仙台、仙台国際センター
  • Year and Date: 2015-04-23
• [Presentation] The frequency of HBV-specific IL10 production and MDSCs might predict the responsiveness of Entercavir-Interferon sequential therapy in chronic hepatitis B patients (2014)
  • Author(s): Yasuteru Kondo, Osamu Kimura, Tomoaki Iwata, Tatsuki Morosawa, Yasuyuki Fujisaka, Takayuki Kogure,Yu Nakagome,Tooru Shimosegawa
  • Organizer: The 11Th JSH Single Topic Conference
  • Place of Presentation: 広島市
  • Year and Date: 2014-11-20 – 2014-11-21
• [Presentation] PD-L1+ MDSCs are likely to become a new biomarker in hepatocellular carcinoma patients (2014)
  • Author(s): Tomoaki Iwata、Yasuteru Kondo、Osamu Kimura, Takayuki Kogure, Tatsuki Morosawa, Yasuyuki Fujisaka, Tooru Shimosegawa
  • Organizer: AASLD2014 Annual Meeting
  • Place of Presentation: ボストン、米国
  • Year and Date: 2014-11-07 – 2014-11-12
• [Presentation] Down regulation of hsa-miR146b-5p might affect the immunopathogenesis of chronic hepatitis C patients (2014)
  • Author(s): Yasuteru Kondo, Masashi Ninomiya, Osamu Kimura, Takayuki Kogure, Yasuhito Tanaka, Yu Nakagome, Tomoaki Iwata, Tatsuki Morosawa, Yasuyuki Fujisaka, Tomoo Kobayashi, Tooru Shimosegawa
  • Organizer: AASLD2014 Annual Meeting
  • Place of Presentation: ボストン、米国
  • Year and Date: 2014-11-07 – 2014-11-12
• [Presentation] 高度線維化症例におけるVitamin D補充の意義 (2014)
  • Author(s): 近藤泰輝、木村修、中込悠、小暮高之、岩田朋晃、諸沢樹、藤坂泰之、小林光樹、佐藤修一、木田真美、小林智夫、宮崎豊、城戸治、小原範之、三浦雅人、涌井裕太、五十嵐勇彦、下瀬川徹
  • Organizer: JDDW2014
  • Place of Presentation: 神戸市
  • Year and Date: 2014-10-24 – 2014-10-26
• [Presentation] B型肝炎の進展、発癌、ETV-IFN Sequential療法効果に影響を与える因子の同定 (2014)
  • Author(s): 近藤泰輝、木村修、中込悠、新妻宏文、二宮匡史、小暮高之、岩田朋晃、諸沢樹、藤坂泰之、渡辺大亮、小林智夫、下瀬川徹
  • Organizer: JDDW2014
  • Place of Presentation: 神戸市
  • Year and Date: 2014-10-23 – 2014-10-26
• [Presentation] HBcAg-specific IL10 production might be an important predictor for the responsiveness to Entercavir-Interferon sequential therapy in chronic hepatitis B patients (2014)
  • Author(s): Yasuteru Kondo, Osamu Kimura, Tomoaki Iwata, Tomoo Kobayashi, Yu Nakagome, Tatsuki Morosawa, Takayuki Kogure, Jun Inoue, Yasuhito Tanaka, Tooru Shimosegawa
  • Organizer: HBV International Meeting on Molecular Biology of Hepatitis B Viruses
  • Place of Presentation: ロサンゼルス、米国
  • Year and Date: 2014-09-03 – 2014-09-06
• [Presentation] 総会長主導企画2 腎疾患における臓器連関の機序と病態発症における意義 肝腎症候群の機序と病態 (2014)
  • Author(s): 近藤泰輝、下瀬川徹
  • Organizer: 日本腎臓学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-07-04 – 2014-07-06
  • Invited
• [Presentation] 肝細胞癌の治療の現状と課題 基調講演 (2014)
  • Author(s): 近藤泰輝
  • Organizer: 日本病院薬剤師会 東北ブロック 第4回学術大会
  • Place of Presentation: 仙台
  • Year and Date: 2014-05-31 – 2014-06-01
  • Invited
• [Presentation] CX3CL1-CX3CR1 axisはB型肝炎、肝癌の免疫病態に影響を与える (2014)
  • Author(s): 近藤泰輝、木村修、岩田朋晃、二宮匡史、諸沢樹、小暮高之、藤坂泰之、新妻宏文、中込悠、下瀬川徹
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-05-29 – 2014-05-30
• [Presentation] 肝細胞癌免疫病態におけるPD-L1+ MDSCsの役割 (2014)
  • Author(s): 岩田朋晃、近藤泰輝、下瀬川徹
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-05-29 – 2014-05-30
• [Presentation] Hepatoma with HBV replication could attract CX3CR1+ NKG2Dlow NK cells and CX3CR1+PD-1+ CD8+ T cells (2014)
  • Author(s): Yasuteru Kondo, Osamu Kimura, Tomoaki Iwata, Tatsuki Morosawa, Masashi Ninomiya, Eiji Kakazu, Takayuki Kogure, Yasuhito Tanaka, Tooru Shimosegawa
  • Organizer: DDW
  • Place of Presentation: シカゴ、米国
  • Year and Date: 2014-05-03 – 2014-05-06
• [Presentation] 進行肝細胞癌患者におけるソラフェニブ血中濃度と免疫病態解析 (2014)
  • Author(s): 近藤泰輝、岩田朋晃、木村修、諸沢樹、藤坂泰之、島田美樹、小暮高之、二宮匡史、下瀬川徹
  • Organizer: 第100回 日本消化器病学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-23 – 2014-04-26
• [Presentation] An appropriate amount of Sorafenib could suppress the myeloid derived suppressor cells (MDSC) and Tregs in HCC patients (2013)
  • Author(s): Kondo Y, Iwata T, Kimura O, Ninomiya M, Morosawa T, Kakazu E, Kogure T, Shimosegawa T
  • Organizer: AASLD Annual Meeting
  • Place of Presentation: ワシントン D.C. アメリカ合衆国
• [Presentation] ソラフェニブの血中濃度と免疫細胞動態からみた効果と副作用の関連 (2013)
  • Author(s): 近藤泰輝、岩田朋晃、下瀬川徹
  • Organizer: 日本肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] 肝細胞癌に誘導されたMyeloid-Derived Suppressor Cells(MDSCs)とPD-L1発現の関係 (2013)
  • Author(s): 岩田 朋晃, 近藤 泰輝, 木村 修, 二宮 匡史, 小暮 高之, 嘉数 英二, 諸沢 樹, 下瀬川 徹
  • Organizer: 日本肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] アンチセンスオリゴヌクレオチドを用いたmiR-221発現抑制による肝癌増殖制御 同所移植マウス肝癌モデルを用いたin vivo研究 (2013)
  • Author(s): 小暮 高之, 近藤 泰輝, 嘉数 英二, 二宮 匡史, 木村 修, 岩田 朋晃, 諸沢 樹, 岩崎 隆雄, 下瀬川 徹
  • Organizer: 日本肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] B型肝炎治療の最前線 免疫反応解析によるETV-IFN Sequential療法効果の予測 (2013)
  • Author(s): 近藤 泰輝, 岩田 朋晃, 下瀬川 徹
  • Organizer: 日本肝臓学会大会
  • Place of Presentation: 東京
• [Book] 新ウイルス性肝炎学（様々な液性因子がB型肝炎免疫病態に与える影響） (2015)
  • Author(s): 近藤泰輝、下瀬川徹
  • Total Pages: 699
  • Publisher: 日本臨床社
• [Remarks] 東北大学 消化器内科 ホームページ
  • URL: http://www.gastroente.med.tohoku.ac.jp
• [Remarks] Researchmap
  • URL: http://researchmap.jp/read0139938/