Designing stakeholder learning dialogues for effective global governance

A growing scholarship on multistakeholder learning dialogues suggests the importance of closely managing learning processes to help stakeholders anticipate which policies are likely to be effective. Much less work has focused on how to manage effective transnational multistakeholder learning dialogues, many of which aim to help address critical global environmental and social problems such as climate change or biodiversity loss. They face three central challenges. First, they rarely shape policies and behaviors directly, but work to ‘nudge’ or ‘tip the scales’ in domestic settings. Second, they run the risk of generating ‘compromise’ approaches incapable of ameliorating the original problem definition for which the dialogue was created. Third, they run the risk of being overly influenced, or captured, by powerful interests whose rationale for participating is to shift problem definitions or narrow instrument choices to those innocuous to their organizational or individual interests. Drawing on policy learning scholarship, we identify a six-stage learning process for anticipating effectiveness designed to minimize these risks while simultaneously fostering innovative approaches for meaningful and longlasting problem solving: Problem definition assessments; Problem framing; Developing coalition membership; Causal framework development; Scoping exercises; Knowledge institutionalization. We also identify six management techniques within each process for engaging transnational dialogues around problem solving. We show that doing so almost always requires anticipating multiple-step causal pathways through which influence of transnational and/or international actors and institutions might occur

NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

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