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.

NASH limits anti-tumour surveillance in immunotherapy-treated HCC / Pfister, D; Nunez, Ng; Pinyol, R; Govaere, O; Pinter, M; Szydlowska, M; Gupta, R; Qiu, Mj; Deczkowska, A; Weiner, A; Muller, 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; Rossler, F; Siebenhuner, A; De Dosso, S; Mallm, Jp; Umansky, V; Jugold, M; Luedde, T; Schietinger, A; Schirmacher, P; Emu, B; Augustin, Hg; Billeter, A; Muller-Stich, B; Kikuchi, H; Duda, Dg; Kutting, F; Waldschmidt, Dt; Ebert, Mp; Rahbari, N; Mei, Hre; Schulz, Ar; Ringelhan, M; Malek, N; Spahn, S; Bitzer, M; de Galarreta, Mr; 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. - In: NATURE. - ISSN 0028-0836. - 592:7854(2021), pp. 450-456. [10.1038/s41586-021-03362-0]

NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Inverso D;
2021-01-01

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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/148259
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