小柯机器人

德国癌症研究中心Mathias Heikenwalder、Josep M. Llovet等研究人员合作发现，NASH限制免疫治疗肝癌中的抗肿瘤监测。2021年3月24日，国际知名学术期刊《自然》在线发表了这一成果。

据研究人员介绍，肝细胞癌（HCC）可能具有病毒和非病毒原因。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，但尚未实现以生物标志物为基础的分层患者，从而对治疗达到最佳反应。

研究人员发现，非常规激活的CD8⁺PD1⁺T细胞在NASH感染的肝脏中出现逐步积累。在NASH诱导的HCC的临床前模型中，针对程序性死亡1（PD1）的治疗性免疫疗法扩大了肿瘤内活化的CD8⁺PD1⁺T细胞的生长，但并未导致肿瘤消退，这表明肿瘤的免疫监测受到损害。如果进行预防性给予，抗PD1治疗会导致NASH-HCC的发生率以及肿瘤结节的数量和大小增加，这与肝CD8⁺PD1⁺CXCR6⁺、TOX⁺和TNF⁺T细胞的增加有关。CD8⁺T细胞耗竭或TNF中和可阻止由抗PD1治疗触发的HCC升高，这表明CD8⁺T细胞有助于诱导NASH-HCC，而不是增强或进行免疫监视。

研究人员在患有NAFLD或NASH的人的肝CD8⁺ PD1⁺ T细胞中发现了相似的表型和功能谱。三项随机III期临床试验的荟萃分析表明，通过在1,600多例晚期HCC患者中测试PDL1（编程性死亡配体1）或PD1的抑制剂，研究人员发现免疫治疗不会提高非病毒性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患者的总生存期降低。

总体而言，这些数据表明，非病毒性肝癌，尤其是NASH-HCC，对免疫疗法的反应可能较弱，这可能是由于NASH相关异常T细胞活化导致组织损伤而导致免疫监视受损。这些数据为免疫治疗研究中的HCC患者分层提供了理论依据。 

附：英文原文

Title: NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author: Dominik Pfister, Nicols Gonzalo Nez, Roser Pinyol, Olivier Govaere, Matthias Pinter, Marta Szydlowska, Revant Gupta, Mengjie Qiu, Aleksandra Deczkowska, Assaf Weiner, Florian Mller, 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, Jrn M. Schattenberg, Michael Allison, Elisabetta Bugianesi, Vlad Ratziu, Tiziana Pressiani, Antonio DAlessio, 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, Jrg Trojan, Kornelius Schulze, Henning Wege, Sandra Koch, Arndt Weinmann, Marco Bueter, Fabian Rssler, Alexander Siebenhner, Sara De Dosso, Jan-Philipp Mallm, Viktor Umansky, Manfred Jugold, Tom Luedde, Andrea Schietinger

Issue&Volume: 2021-03-24

Abstract: Hepatocellular carcinoma (HCC) can have viral or non-viral causes1,2,3,4,5. 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 need6,7. 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.

DOI: 10.1038/s41586-021-03362-0

Source: https://www.nature.com/articles/s41586-021-03362-0

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