The analysis of HCC immune microenvironment after receiving various kinds of HCC treatments for the improvement of iCI treatments

• Project/Area Number: 19K08374
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kumamoto University (2020-2021); Nagoya City University (2019)
• Principal Investigator: Kondo Yasuteru 熊本大学, 大学院生命科学研究部(医), 客員准教授 (70455822)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Tregs / PD-1 / iCIs / MDSCs / Granuloma / CD8 / irAE / PD-L1 / TKIs / HCC / iCI

Outline of Research at the Start

肝細胞癌(HCC)の治療として、免疫チェックポイント阻害剤（iCI）と各種HCC治療併用による高い治療成績が報告された。この要因として、各種HCC治療により、がん免疫微小環境が、iCI治療に好ましい環境へ変化することが想定される。本研究では、背景肝疾患別に、各種HCC治療によるがん免疫微小環境の変化を詳細に検討し、TKI治療などが免疫細胞へ影響を及ぼすメカニズムを解明する。更に、適切にiCIとの併用治療を行う為の基礎となる研究を行い、今後の臨床応用へと発展させたい。

Outline of Final Research Achievements

We could find that the expression of FoxP3 was significantly decreased after the treatment of sorafenib by using deep-sequencing analysis and PBMCs from HCC patients. Then, we carried out immune subsets analysis by using multi-color FACS. We could find that Tregs and MDSCs were significantly decreased after the treatment of sorafenib and Th1 cells was significantly increased after the treatment of sorafenib. Moreover, we demonstrated that the pre-existing ANA and characteristic liver histology including CD8+ cells dominancy and granulomatous hepatitis could be biomarkers for the diagnosis of iCIs-related hepatitis by anti-PD-1 therapy.

Academic Significance and Societal Importance of the Research Achievements

肝細胞癌に対して代表的なTKIであるSorafenibを使用した際にiCIs治療の効果が増強しうる免疫環境に変化することがわかった。現在、様々なiCIs治療のコンビネーションやSequential治療が試みられているが、その際の治療判断の一助になると思われる。また、iCIs治療を行なった際の肝障害に特徴的な肝病理学的組織像も明らかとなったため、早期にステロイド投与の要否の判断が可能となり、より安全にiCIs治療が行えるようになると思われる。

Research Products

• [Journal Article] Identification of microRNA-96-5p as a postoperative, prognostic microRNA predictor in non-viral hepatocellular carcinoma (2022)
  • Author(s): Matsui T, Hamada TS, Naito Y, Nojima M, Iio E, Tamori A, Kubo S, Ide T, Kondo Y, Eguchi Y, Komori A, Morine Y, Shimada M, Utsunomiya T, Kimura K, Hiasa Y, Ochiya T, Naiki A, Takahashi S, Tanaka Y
  • Journal Title: Hepatol Res. Volume: 52(1) Issue: 1 Pages: 93-104
  • DOI: 10.1111/hepr.13674
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anti-nuclear antibody and a granuloma could be biomarkers for iCIs-related hepatitis by anti- PD-1 treatment (2022)
  • Author(s): Kondo Y, Akahira J, Morosawa T, Toi Y, Endo A, Satio H, Endo M, Sugawara S, Tanaka Y
  • Journal Title: Sci Rep. Volume: 12(1) Issue: 1
  • DOI: 10.1038/s41598-022-07770-8
  • Peer Reviewed / Open Access
• [Journal Article] Long-term efficacy and safety of rifaximin in Japanese patients with hepatic encephalopathy: A multicenter retrospective study (2022)
  • Author(s): Kawaratani H, Kondo Y, Tatsumi R, Kawabe N, Tanabe N, Sakamaki A, Okumoto K, Uchida Y, Endo K, Kawaguchi T, Oikawa T, Ishizu Y, Hige S, Takami T, Terai S, Ueno Y, Mochida S, Takikawa Y, Torimura T, Matsuura T, Ishigami M, Koike K, Yoshiji H
  • Journal Title: J Clin Med. Volume: 11(6) Issue: 6 Pages: 1571-1571
  • DOI: 10.3390/jcm11061571
  • Peer Reviewed / Open Access
• [Journal Article] Establishing Efficient Systems through Electronic Medical Records to Promote Intra-hospital Referrals of Hepatitis Virus Carriers to Hepatology Specialists: A Multicenter Questionnaire-based Survey of 1,281 Healthcare Professionals (2021)
  • Author(s): Hidaka I, Enomoto M, Sato S, Suetsugu A, Matono T, Ito K, Ogawa K, Inoue J, Horino M, Kondo Y, Sakaida I, Korenaga M.
  • Journal Title: Internal Medicine Volume: 60 Issue: 3 Pages: 337-343
  • DOI: 10.2169/internalmedicine.4748-20
  • NAID: 130007979716
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-02-01
  • Peer Reviewed
• [Journal Article] Transcriptomics Identify Thrombospondin-2 as a Biomarker for Nonalcoholic Steatohepatitis and Advanced Liver Fibrosis (2021)
  • Author(s): Kozumi K, Kodama T, Murai H, Sakane S, Govaere O, Cockell S, Motooka D, Kakita N, Yamada Y, Kondo Y, Tahata Y, Yamada R, Hikita H, Sakamori R, Kamada Y, Daly KA, Anstee MQ, Tatsumi T, Morii E, Takehara T
  • Journal Title: Hepatology Volume: 74(5) Issue: 5 Pages: 2452-2466
  • DOI: 10.1002/hep.31995
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Proposal of Stroop test cut-off values as screening for neuropsychological impairments in cirrhosis: A Japanese multicenter study (2021)
  • Author(s): Kondo Y, Iwasa M, Kawaratani H, Miyaaki H, Hanai T, Kon K, Hirano H, Shimizu M, Yoshiji H, Okita K, Koike K.
  • Journal Title: Hepatol Res. Volume: - Issue: 6 Pages: 674-681
  • DOI: 10.1111/hepr.13629
  • Peer Reviewed
• [Journal Article] Immune Checkpoint Inhibitor Can Reduce HCV-RNA without Liver Damage (2020)
  • Author(s): Fukuda R, Sugawara S, Kondo Y.
  • Journal Title: Intern Med. Volume: 59(18) Issue: 18 Pages: 2245-2248
  • DOI: 10.2169/internalmedicine.3726-19
  • NAID: 130007904749
  • Peer Reviewed
• [Journal Article] Pilot study of tenofovir disoproxil fumarate and pegylated interferon-alpha 2a add-on therapy in Japanese patients with chronic hepatitis B (2020)
  • Author(s): Matsumoto A, Nishiguchi S, Enomoto H, Tanaka Y, Shinkai N, Okuse C, Kang JH, Matsui T, Miyase S, Yatsuhashi H, Nagaoka S, Kanda T, Enomoto M, Yamada R, Hiramatsu N, Saito S, Takaguchi K, Ito K, Masaki T, Morihara D, Tsuge M, Chayama K, Ikeda F, Kagawa T, Kondo Y, Murata K, Tanaka E.
  • Journal Title: J Gastroenterol. Volume: 55(10) Issue: 10 Pages: 977-989
  • DOI: 10.1007/s00535-020-01707-6
  • Peer Reviewed
• [Journal Article] 免疫チェックポイント阻害剤を使用した際の肝機能障害の特徴 (2020)
  • Author(s): 近藤泰輝、福田遼
  • Journal Title: 肝臓 Volume: 61(3) Pages: 97-98
  • NAID: 130007806187
  • Peer Reviewed
• [Journal Article] 肝細胞癌（HCC）腫瘍マーカー (2020)
  • Author(s): 近藤泰輝 福田遼
  • Journal Title: 臨床消化器内科 Volume: 35(3) Pages: 329-332
• [Journal Article] 肝硬変合併症の診断と治療 （１）肝硬変の腹水治療 (2020)
  • Author(s): 近藤泰輝 諸沢樹
  • Journal Title: 臨床消化器内科 Volume: 35(13) Pages: 1543-1548
• [Journal Article] Hepatitis C virus infection suppresses hepatitis B virus replication via the RIG-I-like helicase pathway (2020)
  • Author(s): Murai Kazuhiro、Hikita Hayato、Kai Yugo、Kondo Yasuteru、Fukuoka Makoto、Fukutomi Keisuke、Doi Akira、Yamai Takuo、Nakabori Tasuku、Fukuda Ryo、Takahashi Takeshi、Miyakawa Kei、Suemizu Hiroshi、Ryo Akihide、Yamada Ryoko、Kodama Takahiro、Sakamori Ryotaro、Tatsumi Tomohide、Takehara Tetsuo
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 941-941
  • DOI: 10.1038/s41598-020-57603-9
  • Peer Reviewed / Open Access
• [Journal Article] 肝細胞癌治療における肝動注療法の最先端 Cutting edge of hepatic artery infusion chemotherapy for hepatocellular carcinoma (2020)
  • Author(s): 近藤泰輝、福田遼
  • Journal Title: 癌と化学療法 Volume: 47 Pages: 1-5
  • Peer Reviewed
• [Journal Article] The reduction of miR146b-5p in monocytes and T cells could contribute to the immunopathogenesis of hepatitis C virus infection (2019)
  • Author(s): Kondo Yasuteru、Kogure Takayuki、Ninomiya Masashi、Fukuda Ryo、Monma Norikazu、Ikeo Kazuho、Tanaka Yasuhito
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 13393-13393
  • DOI: 10.1038/s41598-019-49706-9
  • Peer Reviewed / Open Access
• [Presentation] 非代償性肝硬変マネージメントのコツ(IVR治療を含めた集学的治療） (2021)
  • Author(s): 近藤泰輝
  • Organizer: 第107回 日本消化器病学会総会
  • Invited
• [Presentation] ルストロンボパグとPSE治療の効果と肝癌集学的治療における適切な使用法の解析 (2021)
  • Author(s): 近藤泰輝、諸沢樹、田中靖人
  • Organizer: 第57回 日本肝臓学会総会
• [Presentation] 当院における部分的脾動脈塞栓術の安全性と総リンパ球数を含む血球系へ与える効果の検討 (2021)
  • Author(s): 諸沢樹、近藤泰輝、田中靖人
  • Organizer: 第57回 日本肝臓学会総会
• [Presentation] A multicenter observational study of lenvatinib for unresectable hepatocellular carcinoma in Japan (2021)
  • Author(s): Izumi N, Kudo M, Motomura K, Inaba Y, Katamura Y, Kondo Y, Yabushita K, Motoyoshi K, Furuse J
  • Organizer: ASCO Annual Meeting
  • Int'l Joint Research
• [Presentation] The role of Ablative treatment following TACE/HAIC treatment in the era of MTA and iCIs (2021)
  • Author(s): Kondo Y
  • Organizer: ACTA 2021
  • Int'l Joint Research / Invited
• [Presentation] Ablation therapy could be selected after multidisciplinary treatment including Ultra-FP or DEB-TACE+B-TACE among the BCLC B-D HCC patients (2021)
  • Author(s): Kondo Y
  • Organizer: ACTA 2021
  • Int'l Joint Research
• [Presentation] デバイスとテクニックで広がるRFAの可能性-集学的治療後のアブレーション治療- (2021)
  • Author(s): 近藤泰輝
  • Organizer: JDDW 2021
  • Invited
• [Presentation] Anti-nuclear antibody and a granuloma in the liver could be biomarkers for iCIs-related hepatitis by anti-PD-1 treatment (2021)
  • Author(s): Kondo Y, Morosawa T, Tanaka Y
  • Organizer: AASLD annual meeting 2021
  • Int'l Joint Research
• [Presentation] Ultra-FP treatment could be affordable treatment option for advanced stage of HCC (2021)
  • Author(s): Kondo Y
  • Organizer: APASL oncology 2021
  • Int'l Joint Research
• [Presentation] 免疫チェックポイント阻害剤による肝障害の病理学的特徴 (2020)
  • Author(s): 近藤泰輝、福田遼、田中靖人
  • Organizer: 日本肝臓学会総会2020
• [Presentation] 肝癌の局所治療とその戦略-総括- (2020)
  • Author(s): 近藤泰輝
  • Organizer: 日本肝臓学会総会2020
  • Invited
• [Presentation] DAA治療前後の経時的肝生検による線維化改善に関わるマーカーの探索 (2020)
  • Author(s): 近藤泰輝、福田遼、田中靖人
  • Organizer: 日本肝臓学会総会2020
• [Presentation] 肝癌治療の選択肢を広げるための方策-血小板数に着目して- (2020)
  • Author(s): 近藤泰輝
  • Organizer: JDDW2020
  • Invited
• [Presentation] Drug-Eluting-Beads-HAIC療法とアブレーション治療を主力とした進行肝癌の局所治療の検討 (2020)
  • Author(s): 近藤泰輝、福田遼、田中靖人
  • Organizer: 第43回 日本肝臓学会東部会2020
• [Presentation] 分子標的薬と免疫チェックポイント阻害薬による肝障害：ワークショップ4 (2019)
  • Author(s): 近藤泰輝、福田遼
  • Organizer: 第55回 日本肝臓学会総会
• [Presentation] 進行肝細胞癌におけるレンバチニブ治療の 位置づけと投与法の工夫 (2019)
  • Author(s): 近藤泰輝、福田遼
  • Organizer: 第55回 日本肝臓学会総会
• [Presentation] 肝生検組織を用いたDAA治療前後での肝線維化の検討 (2019)
  • Author(s): 近藤泰輝、福田遼、坂元亨宇
  • Organizer: JDDW 2019
• [Presentation] Anti-nuclear antibody and the CD8/CD4 ratio in the liver could be biomarkers for liver damage induced by anti-PD-1 treatment (2019)
  • Author(s): Yasuteru Kondo, Ryo Fukuda, Junichi Akahira, Mareyuki Endoh, Shunichi Sugawara, Yasuhito Tanaka4
  • Organizer: AASLD Annual meeting 2019
  • Int'l Joint Research
• [Presentation] 肝細胞癌の集学的治療における癌局所療法の役割と今後の展望 (2019)
  • Author(s): 近藤泰輝
  • Organizer: 第41回日本癌局所療法研究会
  • Invited
• [Book] レンバチニブによる肝細胞癌治療: 実臨床におけるレンバチニブ治療の効果と副作用の検討 -免疫学的効果より安全な使用法を模索する- (2019)
  • Author(s): 近藤泰輝、福田遼
  • Total Pages: 4
  • Publisher: アークメディア
• [Book] 臨床消化器内科:免疫チェックポイント阻害薬を使用している患者の肝障害 (2019)
  • Author(s): 近藤 泰輝, 福田 遼 , 永江 真也 , 遠藤 希之, 赤平 純一
  • Total Pages: 4
  • Publisher: 日本メディカルセンター