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BaCKgRoUND aND aIMS:Hepatocellular carcinoma (HCC) is often accompanied by resistance to immunotherapies despite the presence of tumor-infiltrating lymphocytes. We report that histone deacetylase 6 (HDAC6) represses interleukin-17 (IL-17)-producing helper T (T H 17) cell pathogenicity and the antitumor immune response, dependent on its deacetylase activity. appRoaCH aND ReSUltS: Adoptive transfer of HDAC6-deficient T H 17 cells impedes HCC growth, dependent on elevated IL-17A, by enhancing the production of antitumor cytokine and cluster of differentiation 8-positive (CD8+) T cell-mediated antitumor responses. Intriguingly, HDAC6-depleted T cells trigger programmed cell death protein 1 (PD-1)-PD-1 ligand 1 expression to achieve a strong synergistic effect to sensitize advanced HCC to an immune checkpoint blocker, while blockade of IL-17A partially suppresses it. Mechanistically, HDAC6 limits T H 17 pathogenicity and the antitumor effect through regulating forkhead box protein O1 (FoxO1). HDAC6 binds and deacetylates cytosolic FoxO1 at K242, which is required for its nuclear translocation and stabilization to repress retinoic acid-related orphan receptor gamma (RoRγt), the transcription factor of T H 17 cell. This regulation of HDAC6 for murine and human T H 17 cell is highly conserved.CoNClUSIoNS: These results demonstrate that targeting the cytosolic HDAC6-FoxO1 axis reprograms the pathogenicity and antitumor response of T H 17 cells in HCC, with a pathogenicity-driven responsiveness to facilitate immunotherapies (Hepatology 2020;71:1967-1987.

We document a causal effect of the conservative Fox News Channel in the USA on physical distancing during COVID-19 pandemic. We measure county-level mobility covering all US states and District of Columbia produced by GPS pings to 15–17 million smartphones and zip-code-level mobility using Facebook location data. Using the historical position of Fox News Channel in the cable lineup as the source of exogenous variation, we show that increased exposure to Fox News led to a smaller reduction in distance traveled and a smaller increase in the probability of staying home after the national emergency declaration in the USA. Our results show that slanted media can have a harmful effect on containment efforts during a pandemic by affecting people’s behavior.