NASH limits anti-tumour surveillance in immunotherapy-treated HCC.
NASH limits anti-tumour surveillance in immunotherapy-treated HCC.
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DOI：
10.1038/s41586-021-03362-0
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发表时间：
2021-04
期刊：
影响因子：
64.8
通讯作者：
Heikenwalder M
中科院分区：
文献类型：
--
作者：
Pfister D;Núñez NG;Pinyol R;Govaere O;Pinter M;Szydlowska M;Gupta R;Qiu M;Deczkowska A;Weiner A;Müller F;Sinha A;Friebel E;Engleitner T;Lenggenhager D;Moncsek A;Heide D;Stirm K;Kosla J;Kotsiliti E;Leone V;Dudek M;Yousuf S;Inverso D;Singh I;Teijeiro A;Castet F;Montironi C;Haber PK;Tiniakos D;Bedossa P;Cockell S;Younes R;Vacca M;Marra F;Schattenberg JM;Allison M;Bugianesi E;Ratziu V;Pressiani T;D'Alessio A;Personeni N;Rimassa L;Daly AK;Scheiner B;Pomej K;Kirstein MM;Vogel A;Peck-Radosavljevic M;Hucke F;Finkelmeier F;Waidmann O;Trojan J;Schulze K;Wege H;Koch S;Weinmann A;Bueter M;Rössler F;Siebenhüner A;De Dosso S;Mallm JP;Umansky V;Jugold M;Luedde T;Schietinger A;Schirmacher P;Emu B;Augustin HG;Billeter A;Müller-Stich B;Kikuchi H;Duda DG;Kütting F;Waldschmidt DT;Ebert MP;Rahbari N;Mei HE;Schulz AR;Ringelhan M;Malek N;Spahn S;Bitzer M;Ruiz de Galarreta M;Lujambio A;Dufour JF;Marron TU;Kaseb A;Kudo M;Huang YH;Djouder N;Wolter K;Zender L;Marche PN;Decaens T;Pinato DJ;Rad R;Mertens JC;Weber A;Unger K;Meissner F;Roth S;Jilkova ZM;Claassen M;Anstee QM;Amit I;Knolle P;Becher B;Llovet JM;Heikenwalder M
肝细胞癌（HCC）可由病毒或非病毒引起。非酒精性脂肪性肝炎（NASH）是HCC的重要驱动因素。免疫疗法已被批准用于治疗HCC，但基于生物标志物的患者分层对治疗的最佳反应是一个未满足的需求。在这里，我们报告了衰竭的、非常规激活的CD8+PD1+ T细胞在nash影响的肝脏中的渐进式积累。在nash诱导的HCC临床前模型中，靶向程序性死亡-1 （PD1）的治疗性免疫治疗扩大了肿瘤内活化的CD8+PD1+ T细胞，但没有导致肿瘤消退，这表明肿瘤免疫监视功能受损。当预防性给予抗PD1治疗时，NASH-HCC的发病率增加，肿瘤结节的数量和大小增加，这与肝脏CD8+PD1+CXCR6+、TOX+和TNF+ T细胞的增加有关。抗pd1治疗引发的HCC增加可通过CD8+ T细胞耗竭或TNF中和来预防，这表明CD8+ T细胞有助于诱导NASH-HCC，而不是增强或执行免疫监视。我们在NAFLD或NASH患者的肝脏CD8+PD1+ T细胞中发现了相似的表型和功能特征。一项荟萃分析了三个随机III期临床试验，在1600多名晚期HCC患者中测试了PDL1（程序性死亡配体1）或PD1抑制剂，结果显示免疫治疗并没有提高非病毒性HCC患者的生存率。在另外两个队列中，与其他病因的患者相比，接受抗pd1或抗pdl1治疗的nash驱动型HCC患者的总生存率降低。总的来说，这些数据表明，非病毒性HCC，特别是NASH-HCC，可能对免疫治疗反应较差，这可能是由于nash相关的异常T细胞激活导致组织损伤，从而导致免疫监视受损。我们的数据为HCC患者在免疫治疗作为主要或辅助治疗的研究中根据潜在病因进行分层提供了理论依据。在由非酒精性脂肪性肝炎引起的肝细胞癌中，异常的T细胞活化和受损的免疫监视似乎使肝细胞癌对抗pd1或抗pdl1免疫治疗反应较差。
Hepatocellular carcinoma (HCC) can have viral or non-viral causes. 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. 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. In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.
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影响因子：
5.8
作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
Mesirov, Jill P.
DOI：
10.1126/science.1247651
发表时间：
2014-02-14
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Jaitin DA;Kenigsberg E;Keren-Shaul H;Elefant N;Paul F;Zaretsky I;Mildner A;Cohen N;Jung S;Tanay A;Amit I
通讯作者：
Amit I
影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
64.8
作者：
Kang, Tae-Won;Yevsa, Tetyana;Zender, Lars
通讯作者：
Zender, Lars