NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Medientyp: E-Artikel
Titel: NASH limits anti-tumour surveillance in immunotherapy-treated HCC
Beteiligte: Pfister, Dominik; Núñez, Nicolás Gonzalo; Pinyol, Roser; Govaere, Olivier; Pinter, Matthias; Szydlowska, Marta; Gupta, Revant; Qiu, Mengjie; Deczkowska, Aleksandra; Weiner, Assaf; Müller, Florian; Sinha, Ankit; Friebel, Ekaterina; Engleitner, Thomas; Lenggenhager, Daniela; Moncsek, Anja; Heide, Danijela; Stirm, Kristin; Kosla, Jan; Kotsiliti, Eleni; Leone, Valentina; Dudek, Michael; Yousuf, Suhail; Inverso, Donato; [...]
Erschienen: Springer Science and Business Media LLC, 2021
Erschienen in: Nature
Sprache: Englisch
DOI: 10.1038/s41586-021-03362-0
ISSN: 0028-0836; 1476-4687
Schlagwörter: Multidisciplinary
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Beschreibung: <jats:title>Abstract</jats:title><jats:p>Hepatocellular carcinoma (HCC) can have viral or non-viral causes<jats:sup>1–5</jats:sup>. 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<jats:sup>6,7</jats:sup>. Here we report the progressive accumulation of exhausted, unconventionally activated CD8<jats:sup>+</jats:sup>PD1<jats:sup>+</jats:sup>T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8<jats:sup>+</jats:sup>PD1<jats:sup>+</jats:sup>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<jats:sup>+</jats:sup>PD1<jats:sup>+</jats:sup>CXCR6<jats:sup>+</jats:sup>, TOX<jats:sup>+</jats:sup>, and TNF<jats:sup>+</jats:sup>T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8<jats:sup>+</jats:sup>T cells or TNF neutralization, suggesting that CD8<jats:sup>+</jats:sup>T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8<jats:sup>+</jats:sup>PD1<jats:sup>+</jats:sup>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.</jats:p>

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