| Authors: |
Pfister, D.; Núñez, N. G.; 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, P. K.; Tiniakos, D.; Bedossa, P.; Cockell, S.; Younes, R.; Vacca, M.; Marra, F.; Schattenberg, J. M.; Allison, M.; Bugianesi, E.; Ratziu, V.; Pressiani, T.; D’Alessio, A.; Personeni, N.; Rimassa, L.; Daly, A. K.; Scheiner, B.; Pomej, K.; Kirstein, M. M.; 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, J. P.; Umansky, V.; Jugold, M.; Luedde, T.; Schietinger, A.; Schirmacher, P.; Emu, B.; Augustin, H. G.; Billeter, A.; Müller-Stich, B.; Kikuchi, H.; Duda, D. G.; Kütting, F.; Waldschmidt, D. T.; Ebert, M. P.; Rahbari, N.; Mei, H. E.; Schulz, A. R.; Ringelhan, M.; Malek, N.; Spahn, S.; Bitzer, M.; Ruiz de Galarreta, M.; Lujambio, A.; Dufour, J. F.; Marron, T. U.; Kaseb, A.; Kudo, M.; Huang, Y. H.; Djouder, N.; Wolter, K.; Zender, L.; Marche, P. N.; Decaens, T.; Pinato, D. J.; Rad, R.; Mertens, J. C.; Weber, A.; Unger, K.; Meissner, F.; Roth, S.; Jilkova, Z. M.; Claassen, M.; Anstee, Q. M.; Amit, I.; Knolle, P.; Becher, B.; Llovet, J. M.; Heikenwalder, M. |
| Article Title: |
NASH limits anti-tumour surveillance in immunotherapy-treated HCC |
| Abstract: |
Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. 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. © 2021, The Author(s). |
| Journal Title: |
Nature
|
| Volume: |
592 |
| Issue: |
7854 |
| ISSN: |
0028-0836 |
| Publisher: |
Nature Publishing Group
|
| Date Published: |
2021-04-15 |
| Start Page: |
450 |
| End Page: |
456 |
| Language: |
English |
| DOI: |
10.1038/s41586-021-03362-0
|
| PUBMED: |
33762733
|
| PROVIDER: |
scopus
|
| PMCID: |
PMC8046670
|
| DOI/URL: |
|
| Notes: |
Article -- Export Date: 3 May 2021 -- Source: Scopus |
