This is the report of a preclinical and clinical work assessing the potential correlation between NASH-driven hepatocellular carcinoma (HCC) and response to immunotherapy. In preclinical models of NASH-induced HCC, immunotherapy targeted at PD-1 expanded activated CD8+PD1+ T cells in the tumors but did not lead to tumor regression, indicating that tumor immune surveillance was impaired. A meta-analysis of 3 randomized phase 3 trials testing anti-PD-1/PD-L1 in >1,600 patients with advanced HCC showed that the treatment did not improve overall survival (OS) in patients with non-viral HCC. Also, 2 additional cohorts of patients with NASH-driven HCC treated with anti-PD-1/PD-L1 showed reduced OS compared to patients with other etiologies. These data show that non-viral/NASH-HCC might be less responsive to immunotherapy, due to aberrant T cell activation and impaired immune surveillance, providing a rationale for stratification according to HCC etiology in studies of immunotherapy.

(Pfister, D. et al. – Nature, April 2021)

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