T-cell Dysfunction Limits Immunotherapy Efficacy in NASH-Induced Liver Cancer

Hepatocellular carcinoma (HCC) can arise from several underlying conditions, such as viral infection and nonalcoholic steatohepatitis (NASH). Whether disease etiology underlies some of the differences in treatment efficacy among patients with HCC is unknown. To investigate this, Pfister and colleagues fed mice a NASH-inducing diet and found that these mice had higher levels of CD8⁺PD-1⁺ T cells in their livers, suggesting that HCC associated with NASH may be more responsive to immunotherapy targeting the PD-1–PD-L1 axis. On the contrary, unlike mice with liver cancer not caused by NASH, liver tumors in mice fed the NASH-associated diet did not respond to anti–PD-1 treatment—instead, livers in these mice exhibited a greater degree of fibrosis and no change in tumor burden. Further, depletion of CD8⁺ T cells in mice with NASH but not HCC led to reduced liver damage and lower incidence of NASH-induced HCC, implying that CD8⁺ T cells not only are ineffective in controlling liver tumors in this setting, but also actively promote cancer in NASH-induced HCC. Further analyses revealed that CD8⁺PD-1⁺ T cells in the livers of mice with NASH-induced HCC had increased expression of effector and exhaustion markers and that anti–PD-1 treatment caused accumulation of CD8⁺PD-1⁺ T cells (many of which expressed the tissue-residency marker FOXO1) in the liver. Additionally, the livers of patients with NASH had increased numbers of CD8⁺PD-1⁺ T cells exhibiting a tissue-residency phenotype relative to the livers of healthy control subjects, and these NASH-associated T cells had gene expression profiles similar to those of liver T cells from the mouse model of NASH. In a meta-analysis of data from three randomized, controlled trials of immunotherapies in patients with HCC, substantial heterogeneity was identified in response according to etiology, with a significantly decreased benefit found in patients with nonviral etiologies when compared with viral etiologies. Finally, in two independent cohorts of patients with HCC, anti–PD-1 or anti–PD-L1 treatment was associated with shorter overall survival in patients with NASH-associated HCC compared with patients with HCC of other etiologies. Together, these findings reveal why immunotherapy may be less effective in patients with nonviral HCC.

Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M, Szydlowska M, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 2021 Mar 24 [Epub ahead of print].

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