肝細胞がんに対する免疫療法

いつも記事を読んでくださり、ありがとうございます。

癌治療における免疫治療は化学療法(抗がん剤など)
放射線療法、外科治療に次ぐ第４の治療法として
近年注目されています。
筆者の感覚としては、一昨年くらいから
癌治療に対する免疫療法の位置づけが変わってきている
と科学論文を継続的にモニターにしている中で感じます。
基本的に免疫機能は体内に普遍的に存在するもので
身体を病原体などの外敵、あるいは
遺伝子改変などでできた異常な組織に対して
正常な状態に戻すように働きます。
そういった場合、免疫細胞の種類、表現型、極性などにおいて
改変を加えることで異常な状態に対峙しますが、
その状態変化が慢性化していたり、程度が大きい場合には
副作用、副反応もあると思っています。
従って、免疫治療を考える場合には
常に「均衡状態、バランス」を評価していく事が大事になる
と考えています。
ーーーーーーーー
Dominik Pfister, Nicolás Gonzalo Núñez, Roser Pinyol
(敬称略)らからなる
ドイツ、スイス、スペイン、イギリス、オーストリア
イスラエル、アメリカ、ギリシャ、イタリア、
日本(大阪)、台湾、フランスの
国際的な医療研究グループは
非アルコール性脂肪性肝炎起因の肝細胞癌に対して
免疫チェックポイント阻害薬を使用した場合において
惹起された免疫細胞の表現型
それに対する臨床効果について詳しく報告されています(1)。
本日はその内容の一部について
筆者の視点で追記しながら読者の方と情報共有したいと思います。
ーーーーーーーー

//概要//ーーーーー
肝細胞癌はウィルス性と非ウィルス性があります(2-6)。
非アルコール性脂肪性肝炎は肝細胞癌への発展において
主要な作動因子となります。
例えば、参考文献(7)Fig.1に示されているように
慢性肝炎から肝硬変に移行し、そこから肝臓癌に発展します。
その肝細胞癌において免疫療法は承認されていますが、
バイオマーカーによる患者さんの分類、層化が
医療現場では強く求められています(8,9)。
--
免疫療法の一つの大きな枠組みである
免疫チェックポイント阻害薬による治療は
肝細胞癌に関しては
・CD8+PD1+CXCR6+T細胞 
・TOX+T細胞 , 
・TNF+T細胞
これらを惹起する事がわかっています(1)。
これらのT細胞は肝細胞癌を退行させるよりも
逆に成長させる事に繋がると考えらています。
従って、
特に非アルコール性脂肪性肝炎起因の肝細胞癌に関しては
免疫チェックポイント阻害薬で治療した場合には
生存率を下げる事が治験で示されています。
(参考文献(1) Fig.4b,cより)
ゆえにT細胞の異常活性が考えられるため
制御性T細胞を特異的に生み出し、均衡状態を保つような
アドジュバント、補助療法が必要になる可能性があります。
また非アルコール性脂肪性肝炎起因の肝細胞癌に対する
免疫治療は向いていない可能性があります。
ーーーーー

//幹細胞癌に進行する想定される生理機序//ーーーーー
・自然免疫系統の活性化(10-12)
・獲得免疫系統の活性化(10-12)
・代謝生成物の増加
・細胞内の小胞体ストレス(11,13)
これらにより肝細胞死を導く炎症や
肝細胞癌組織の再生などにつながります(14-16)。
ーーーーー

//肝細胞癌を抑制する因子//ーーーーー
Anti-CD8+抗体
これにより癌細胞の病変部位は
コントロール群に対して有意に抑えられています。
さらにNK1.1+細胞を加えれば
肝細胞癌の発現確率を下げる可能性があります。
(参考文献(1) Fig.2i)
ーーーーー

//CD8+PD1+T細胞の特性//ーーーーー
このT細胞は組織移住性を有しており、
発現量が多くなった時、肝臓組織に蓄積する事が知られています。
肝臓組織に結合するとされる因子は
CD44, CXCR6, EOMES and TOX
これらとなっています。
(参考文献(1)Extended Data Fig. 6) 
これらの遺伝子のうち表面で発現されるものは
モノクローナル抗体や細胞特異的輸送系統の標的となります。
--
この細胞は人のケースにおいて
肝細胞の損傷と正の相関があり、バイオマーカーとなります。
ーーーーー

//細胞特異的輸送系統//ーーーーーーーー
肝細胞癌の特徴として免疫監視が崩壊することで
細胞傷害性CD8+T細胞の数が異常に増え
組織損傷を招き、癌化を促進する事が考えられます。
このCD8+T細胞や他のT細胞は
肝細胞癌組織近くに多く存在しますから
そのT細胞の特異的エピトープを標的とした
ナノ粒子表面装飾を行い、
それらのT細胞の活性を制御しつつ、
肝細胞癌付近で抗がん剤による科学療法を行います。
従って、薬剤輸送媒体が惹起されたT細胞に結合した時点で
その輸送媒体の表面膜が破れ、
中の薬剤が癌組織付近で放出されるという仕組みです。
ーーーーーーーー

以上です。

(参考文献)
(1)
Dominik Pfister, Nicolás Gonzalo Núñez, Roser Pinyol, Olivier Govaere, Matthias Pinter, Marta Szydlowska, Revant Gupta, Mengjie Qiu, Aleksandra Deczkowska, Assaf Weiner, Florian Müller, Ankit Sinha, Ekaterina Friebel, Thomas Engleitner, Daniela Lenggenhager, Anja Moncsek, Danijela Heide, Kristin Stirm, Jan Kosla, Eleni Kotsiliti, Valentina Leone, Michael Dudek, Suhail Yousuf, Donato Inverso, Indrabahadur Singh, Ana Teijeiro, Florian Castet, Carla Montironi, Philipp K. Haber, Dina Tiniakos, Pierre Bedossa, Simon Cockell, Ramy Younes, Michele Vacca, Fabio Marra, Jörn M. Schattenberg, Michael Allison, Elisabetta Bugianesi, Vlad Ratziu, Tiziana Pressiani, Antonio D’Alessio, Nicola Personeni, Lorenza Rimassa, Ann K. Daly, Bernhard Scheiner, Katharina Pomej, Martha M. Kirstein, Arndt Vogel, Markus Peck-Radosavljevic, Florian Hucke, Fabian Finkelmeier, Oliver Waidmann, Jörg Trojan, Kornelius Schulze, Henning Wege, Sandra Koch, Arndt Weinmann, Marco Bueter, Fabian Rössler, Alexander Siebenhüner, Sara De Dosso, Jan-Philipp Mallm, Viktor Umansky, Manfred Jugold, Tom Luedde, Andrea Schietinger, Peter Schirmacher, Brinda Emu, Hellmut G. Augustin, Adrian Billeter, Beat Müller-Stich, Hiroto Kikuchi, Dan G. Duda, Fabian Kütting, Dirk-Thomas Waldschmidt, Matthias Philip Ebert, Nuh Rahbari, Henrik E. Mei, Axel Ronald Schulz, Marc Ringelhan, Nisar Malek, Stephan Spahn, Michael Bitzer, Marina Ruiz de Galarreta, Amaia Lujambio, Jean-Francois Dufour, Thomas U. Marron, Ahmed Kaseb, Masatoshi Kudo, Yi-Hsiang Huang, Nabil Djouder, Katharina Wolter, Lars Zender, Parice N. Marche, Thomas Decaens, David J. Pinato, Roland Rad, Joachim C. Mertens, Achim Weber, Kristian Unger, Felix Meissner, Susanne Roth, Zuzana Macek Jilkova, Manfred Claassen, Quentin M. Anstee, Ido Amit, Percy Knolle, Burkhard Becher, Josep M. Llovet & Mathias Heikenwalder 
NASH limits anti-tumour surveillance in immunotherapy-treated HCC
Nature (2021)
ーーーーーーーー
Affiliations
Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
Dominik Pfister, Marta Szydlowska, Florian Müller, Danijela Heide, Kristin Stirm, Jan Kosla, Eleni Kotsiliti, Valentina Leone, Indrabahadur Singh, Brinda Emu & Mathias Heikenwalder
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
Nicolás Gonzalo Núñez, Ekaterina Friebel & Burkhard Becher
Liver Cancer Translational Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Liver Unit, Universitat de Barcelona, Barcelona, Spain
Roser Pinyol, Florian Castet, Carla Montironi & Josep M. Llovet
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK
Olivier Govaere, Dina Tiniakos, Pierre Bedossa, Ramy Younes, Ann K. Daly & Quentin M. Anstee
Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
Matthias Pinter, Bernhard Scheiner & Katharina Pomej
Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
Matthias Pinter, Bernhard Scheiner & Katharina Pomej
Internal Medicine I, University Hospital Tübingen, Faculty of Medicine, University of Tübingen, Tübingen, Germany
Revant Gupta & Manfred Claassen
Department of Computer Science, University of Tübingen, Tübingen, Germany
Revant Gupta & Manfred Claassen
Department of General, Visceral and Transplantation Surgery, Universitätsklinikum Heidelberg, Heidelberg, Germany
Mengjie Qiu, Suhail Yousuf & Susanne Roth
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
Aleksandra Deczkowska, Assaf Weiner & Ido Amit
Experimental Systems Immunology Laboratory, Max-Planck Institute of Biochemistry, Munich, Germany
Ankit Sinha & Felix Meissner
Institute of Translational Cancer Research and Experimental Cancer Therapy, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
Ankit SinhaCenter for Translational Cancer Research (TranslaTUM), Technical University Munich, Munich, Germany
Thomas Engleitner & Roland Rad
Department of Medicine II, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany
Thomas Engleitner & Roland Rad
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Munich, Germany
Thomas Engleitner & Roland Rad
Department of Pathology and Molecular Pathology, University and University Hospital Zurich, Zurich, Switzerland
Daniela Lenggenhager & Achim Weber
Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
Anja Moncsek & Joachim C. Mertens
Research Unit of Radiation Cytogenetics, Helmholtz Zentrum Munich, Munich, Germany
Valentina Leone & Kristian Unger
Institute of Molecular Immunology and Experimental Oncology, Technical University Munich, Munich, Germany
Michael Dudek & Percy Knolle
Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
Donato Inverso & Hellmut G. Augustin
European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
Donato Inverso & Hellmut G. Augustin
Emmy Noether Research Group Epigenetic Machineries and Cancer, Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
Indrabahadur Singh
Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Spanish National Cancer Research Centre, CNIO, Madrid, Spain
Ana Teijeiro & Nabil Djouder
Mount Sinai Liver Cancer Program, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Philipp K. Haber, Marina Ruiz de Galarreta, Amaia Lujambio, Thomas U. Marron & Josep M. Llovet
Department of Pathology, Aretaeion Hospita, National and Kapodistrian University of Athens, Athens, Greece
Dina Tiniakos
Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle, UK
Simon Cockell
Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turn, Italy
Ramy Younes & Elisabetta Bugianesi
University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
Michele Vacca
Dipartimento di Medicina Sperimentale e Clinica, University of Florence, Florence, Italy
Fabio Marra
Metabolic Liver Research Program, I. Department of Medicine, University Medical Center Mainz, Mainz, Germany
Jörn M. Schattenberg
Liver Unit, Department of Medicine, Cambridge Biomedical Research Centre, Cambridge University NHS Foundation Trust, Cambridge, UK
Michael Allison
Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, University Paris-Diderot, Paris, France
Vlad Ratziu
Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Milan, Italy
Tiziana Pressiani, Antonio D’Alessio, Nicola Personeni & Lorenza Rimassa
Department of Biomedical Sciences, Humanitas University, Milan, Italy
Nicola Personeni & Lorenza Rimassa
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
Martha M. Kirstein & Arndt Vogel
University Medical Center Schleswig-Holstein, Schleswig-Holstein, Germany
Martha M. Kirstein
Department of Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
Markus Peck-Radosavljevic & Florian Hucke
Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt, Germany
Fabian Finkelmeier, Oliver Waidmann & Jörg Trojan
Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Kornelius Schulze & Henning Wege
Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Sandra Koch & Arndt Weinmann
Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
Marco Bueter & Fabian Rössler
Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
Alexander Siebenhüner
Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
Sara De Dosso
Division of Chromatin Networks, German Cancer Research Center (DKFZ) and Bioquant, Heidelberg, Germany
Jan-Philipp Mallm
Clinical Cooperation Unit Dermato-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Viktor Umansky
Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany
Viktor Umansky
Core Facility Small Animal Imaging, German Cancer Research Center Heidelberg, Heidelberg, Germany
Manfred Jugold
Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Tom Luedde
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Andrea Schietinger
Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
Andrea Schietinger
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Peter Schirmacher
Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
Adrian Billeter & Beat Müller-Stich
Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
Hiroto Kikuchi & Dan G. Duda
Department of Gastroenterology and Hepatology, University of Cologne, Cologne, Germany
Fabian Kütting & Dirk-Thomas Waldschmidt
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
Matthias Philip Ebert
Department of Surgery at University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
Nuh Rahbari
Mass Cytometry Lab, Deutsches Rheumaforschungszentrum Berlin, a Leibniz Institute, Berlin, Germany
Henrik E. Mei & Axel Ronald Schulz
Institute of Virology, Technical University Munich/Helmholtz Zentrum Munich, Munich, Germany
Marc Ringelhan
Department of Internal Medicine II, University Hospital rechts der Isar, Technical University Munich, Munich, Germany
Marc Ringelhan
German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
Marc Ringelhan
Medical University Hospital Department of Internal Medicine I, Tübingen, Germany
Nisar Malek, Stephan Spahn & Michael Bitzer
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Marina Ruiz de Galarreta & Amaia Lujambio
The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Amaia Lujambio
University Clinic for Visceral Surgery and Medicine, Inselspital, Bern, Switzerland
Jean-Francois Dufour
Hepatology, Department of Biomedical Research, University of Bern, Bern, Switzerland
Jean-Francois Dufour
Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA
Thomas U. Marron
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Ahmed Kaseb
Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-, Sayama, Japan
Masatoshi Kudo
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
Yi-Hsiang Huang
Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
Yi-Hsiang Huang
Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen, Germany
Katharina Wolter & Lars Zender
Cluster of Excellence ‘Image Guided and Functionally Instructed Tumor Therapies’ (iFIT), Eberhard-Karls University of Tübingen, Tübingen, Germany
Katharina Wolter & Lars Zender
German Consortium for Translational Cancer Research (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), Tübingen, Germany
Lars Zender
Université Grenoble Alpes, Grenoble, France
Parice N. Marche, Thomas Decaens & Zuzana Macek Jilkova
Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309, Grenoble, France
Parice N. Marche, Thomas Decaens & Zuzana Macek Jilkova
Service d’hépato-gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, Grenoble, France
Thomas Decaens
Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
David J. Pinato & Zuzana Macek Jilkova
Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
David J. Pinato
Institute of Molecular Cancer Research (IMCR), University of Zurich, Zurich, Switzerland
Achim Weber
Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle, UK
Quentin M. Anstee
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
Josep M. Llovet
ーーーーーーーー

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