COVID-19 disease, caused by SARS-CoV-2 infection, has resulted in more than 15.5 million infections and 634,000 deaths worldwide. A recent study of hospitals in New York City, at the initial epicenter of the COVID-19 pandemic in the United States, reported that, during March 2020, 21% of patients hospitalized with confirmed COVID-19 died 1 . These findings are aligned with outcomes observed in the Mount Sinai Health System 2,3 . There are currently no curative or preventive therapies for COVID-19, highlighting the need to enhance current understanding of SARS-CoV-2 pathogenesis for the rational development of therapeutics.Recent studies have suggested that, in addition to direct viral damage, uncontrolled inflammation contributes to disease severity in 5 ). Consistent with this hypothesis, high levels of inflammatory markers, including C-reactive protein (CRP), ferritin and D-dimer, high neutrophil-to-lymphocyte ratio [6][7][8][9] and increased levels of inflammatory cytokines and chemokines 6,8-11 have been observed in patients with severe diseases. Pathogenic inflammation, also referred to as cytokine storm, shares similarities with what was previously seen in patients infected with other severe coronaviruses, including SARS-CoV and Middle East respiratory syndrome coronavirus 12 , and bears similarities to cytokine release syndrome (CRS) observed in patients with cancer treated with chimeric antigen receptor-modified (CAR) T cells 13 . Tocilizumab, an IL-6 receptor inhibitor, is a US Food and Drug Administration (FDA)-approved treatment for CRS in patients receiving CAR T cells 14 . Several single-center studies have used IL-6 inhibitors to treat patients with COVID-19 with some clinical benefits 15 and reported failures 14 . Beyond IL-6, several cytokines have been shown to be elevated in CRS and to contribute to tissue damage. TNF-α is important in nearly all acute inflammatory reactions, acting as an amplifier of inflammation. TNF-α blockade has been used to treat more than ten different autoimmune inflammatory diseases, suggesting that this might be a potential therapeutic approach to reduce organ damage in patients with ). IL-1 is also a highly active pro-inflammatory cytokine, and monotherapy blocking

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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