NASH limits anti-tumour surveillance in immunotherapy-treated HCC

被引:825
作者
Pfister, Dominik [1 ,85 ]
Nunez, Nicolas Gonzalo [2 ]
Pinyol, Roser [3 ]
Govaere, Olivier [4 ]
Pinter, Matthias [5 ,6 ]
Szydlowska, Marta [1 ]
Gupta, Revant [7 ,8 ]
Qiu, Mengjie [9 ]
Deczkowska, Aleksandra [10 ]
Weiner, Assaf [10 ]
Mueller, Florian [1 ]
Sinha, Ankit [11 ,12 ]
Friebel, Ekaterina [2 ]
Engleitner, Thomas [13 ,14 ,15 ]
Lenggenhager, Daniela [16 ,17 ]
Moncsek, Anja [18 ]
Heide, Danijela [1 ]
Stirm, Kristin [1 ]
Kosla, Jan [1 ]
Kotsiliti, Eleni [1 ]
Leone, Valentina [1 ,19 ]
Dudek, Michael [20 ]
Yousuf, Suhail [9 ]
Inverso, Donato [21 ,22 ]
Singh, Indrabahadur [1 ,23 ]
Teijeiro, Ana [24 ]
Castet, Florian [3 ]
Montironi, Carla [3 ]
Haber, Philipp K. [25 ]
Tiniakos, Dina [4 ,26 ]
Bedossa, Pierre [4 ]
Cockell, Simon [27 ]
Younes, Ramy [4 ,28 ]
Vacca, Michele [29 ]
Marra, Fabio [30 ]
Schattenberg, Jorn M. [31 ]
Allison, Michael [32 ]
Bugianesi, Elisabetta [28 ]
Ratziu, Vlad [33 ]
Pressiani, Tiziana [34 ]
D'Alessio, Antonio [34 ]
Personeni, Nicola [34 ,35 ]
Rimassa, Lorenza [34 ,35 ]
Daly, Ann K. [4 ]
Scheiner, Bernhard [5 ,6 ]
Pomej, Katharina [5 ,6 ]
Kirstein, Martha M. [36 ,37 ]
Vogel, Arndt [36 ]
Peck-Radosavljevic, Markus [38 ]
Hucke, Florian [38 ]
机构
[1] German Canc Res Ctr, Div Chron Inflammat & Canc, Heidelberg, Germany
[2] Univ Zurich, Inst Expt Immunol, Zurich, Switzerland
[3] Univ Barcelona, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Liver Unit, Liver Canc Translat Res Lab,Hosp Clin, Barcelona, Spain
[4] Newcastle Univ, Translat & Clin Res Inst, Fac Med Sci, Newcastle, England
[5] Med Univ Vienna, Div Gastroenterol & Hepatol, Dept Internal Med 3, Vienna, Austria
[6] Med Univ Vienna, Liver Canc HCC Study Grp Vienna, Vienna, Austria
[7] Univ Tubingen, Univ Tubingen Hosp, Internal Med 1, Fac Med, Tubingen, Germany
[8] Univ Tubingen, Dept Comp Sci, Tubingen, Germany
[9] Univ Klinikum Heidelberg, Dept Gen Visceral & Transplantat Surg, Heidelberg, Germany
[10] Weizmann Inst Sci, Dept Immunol, Rehovot, Israel
[11] Max Planck Inst Biochem, Expt Syst Immunol Lab, Munich, Germany
[12] Tech Univ Munich, Inst Translat Canc Res & Expt Canc Therapy, Klinikum Rechts Isar, Munich, Germany
[13] Tech Univ Munich, Ctr Translat Canc Res TranslaTUM, Munich, Germany
[14] Tech Univ Munich, Dept Med 2, Klinikum Rechts Isar, Munich, Germany
[15] German Canc Res Ctr, German Canc Consortium DKTK, Munich, Germany
[16] Univ Zurich, Dept Pathol & Mol Pathol, Zurich, Switzerland
[17] Univ Hosp Zurich, Zurich, Switzerland
[18] Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Zurich, Switzerland
[19] Helmholtz Zentrum Munich, Res Unit Radiat Cytogenet, Munich, Germany
[20] Tech Univ Munich, Inst Mol Immunol & Expt Oncol, Munich, Germany
[21] German Canc Res Ctr DKFZ ZMBH Alliance, Div Vasc Oncol & Metastasis, Heidelberg, Germany
[22] Heidelberg Univ, Med Fac Mannheim, European Ctr Angiosci ECAS, Heidelberg, Germany
[23] German Canc Res Ctr, Div Chron Inflammat & Canc, Emmy Noether Res Grp Epigenet Machineries & Canc, Heidelberg, Germany
[24] CNIO, Growth Factors Nutrients & Canc Grp, Spanish Natl Canc Res Ctr, Cell Biol Programme, Madrid, Spain
[25] Icahn Sch Med Mt Sinai, Div Liver Dis, Mt Sinai Liver Canc Program, New York, NY 10029 USA
[26] Natl & Kapodistrian Univ Athens, Aretae Hospita, Dept Pathol, Athens, Greece
[27] Newcastle Univ, Bioinformat Support Unit, Fac Med Sci, Newcastle, England
[28] Univ Turin, Div Gastrohepatol, Dept Med Sci, AO Citta Salute & Sci Torino, Turn, Italy
[29] Univ Cambridge, Wellcome MRC Inst Metab Sci, Addenbrookes Hosp, Metab Res Labs, Cambridge, England
[30] Univ Florence, Dipartimento Med Sperimentale Clin, Florence, Italy
[31] Univ Med Ctr Mainz, Dept Med 1, Metab Liver Res Program, Mainz, Germany
[32] Cambridge Univ NHS Fdn Trust, Dept Med, Liver Unit, Cambridge Biomed Res Ctr, Cambridge, England
[33] Univ Paris Diderot, Hop Beaujon, AP HP, Paris, France
[34] Humanitas Clin & Res Ctr IRCCS, Med Oncol & Hematol Unit, Humanitas Canc Ctr, Milan, Italy
[35] Humanitas Univ, Dept Biomed Sci, Milan, Italy
[36] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany
[37] Univ Med Ctr Schleswig Holstein, Schleswig Holstein, Germany
[38] Klinikum Klagenfurt Worthersee, Hepatol Endocrinol Rheumatol & Nephrol Including, Dept Internal Med & Gastroenterol IMuG, Klagenfurt, Austria
[39] Univ Hosp Frankfurt, Dept Gastroenterol Hepatol & Endocrinol, Frankfurt, Germany
[40] Univ Med Ctr Hamburg Eppendorf, Dept Internal Med Gastroenterol & Hepatol, Hamburg, Germany
[41] Johannes Gutenberg Univ Mainz, Dept Internal Med, Univ Med Ctr, Mainz, Germany
[42] Univ Hosp Zurich, Dept Surg & Transplantat, Zurich, Switzerland
[43] Univ Hosp Zurich, Dept Med Oncol & Hematol, Zurich, Switzerland
[44] Univ Zurich, Zurich, Switzerland
[45] Oncol Inst Southern Switzerland, Bellinzona, Switzerland
[46] German Canc Res Ctr, Div Chromatin Networks, Heidelberg, Germany
[47] Bioquant, Heidelberg, Germany
[48] German Canc Res Ctr, Clin Cooperat Unit Dermatooncol, Heidelberg, Germany
[49] Ruprecht Karl Univ Heidelberg, Univ Med Ctr Mannheim, Dept Dermatol Venereol & Allergol, Heidelberg, Germany
[50] German Canc Res Ctr Heidelberg, Core Facil Small Anim Imaging, Heidelberg, Germany
基金
欧盟地平线“2020”; 瑞士国家科学基金会; 以色列科学基金会; 欧洲研究理事会; 英国惠康基金;
关键词
ADVANCED HEPATOCELLULAR-CARCINOMA; LIVER-CANCER; NONALCOHOLIC STEATOHEPATITIS; PHASE-III; R PACKAGE; T-CELLS; RNA-SEQ; NAFLD;
D O I
10.1038/s41586-021-03362-0
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Hepatocellular carcinoma (HCC) can have viral or non-viral causes(1-5). Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need(6,7). Here we report the progressive accumulation of exhausted, unconventionally activated CD8(+)PD1(+) T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8(+)PD1(+) T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8(+)PD1(+)CXCR6(+), TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8(+) T cells or TNF neutralization, suggesting that CD8(+) T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8(+)PD1(+) T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.
引用
收藏
页码:450 / 456
页数:7
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