NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Hepatocellular carcinoma (HCC) can have viral or non-viral causes(1-5). 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 need(6,7). 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

Non-microbial methane formation in oxic soils

Methane plays an important role as a radiatively and chemically active gas in our atmosphere. Until recently, sources of atmospheric methane in the biosphere have been attributed to strictly anaerobic microbial processes during degradation of organic matter. However, a large fraction of methane produced in the anoxic soil layers does not reach the atmosphere due to methanotrophic consumption in the overlaying oxic soil. Although methane fluxes from aerobic soils have been observed, an alternative source other than methanogenesis has not been identified thus far. <br></br> Here we provide evidence for non-microbial methane formation in soils under oxic conditions. We found that soils release methane upon heating and other environmental factors like ultraviolet irradiation, and drying-rewetting cycles. We suggest that chemical formation of methane during degradation of soil organic matter may represent the missing soil source that is needed to fully understand the methane cycle in aerobic soils. Although the emission fluxes are relatively low when compared to those from wetlands, they may be important in warm and wet regions subjected to ultraviolet radiation. We suggest that this methane source is highly sensitive to global change

Manganese (Mn)-enhanced magnet resonance imaging (MRI) for in vivo assessment of tissue regeneration following neuronal precursor cell transplantation after cervical spinal cord injury in rats

W.M. McPheeters, 1840