Endoplasmic reticulum (ER) stress promotes tumor cell escape from immunosurveillance. However, the underlying mechanisms remain unknown. We hypothesized that ER stress induces hepatocellular carcinoma (HCC) cells to release exosomes, which attenuate antitumor immunity by modulating the expression of programmed death ligand 1 (PD‐L1) in macrophages. In this study, we demonstrated that expression of several ER stress markers (glucose‐regulated protein 78, activating transcription factor 6, protein kinase R–like ER kinase, and inositol‐requiring enzyme 1α) was up‐regulated in HCC tissues and negatively correlated with the overall survival and clinicopathological scores in patients with HCC. Expression of ER stress–related proteins positively correlated with CD68+ macrophage recruitment and PD‐L1 expression in HCC tissues. High‐throughput sequencing analysis identified miR‐23a‐3p as one of the most abundant microRNAs in exosomes derived from tunicamycin (TM)‐treated HCC cells (Exo‐TMs). miR‐23a‐3p levels in HCC tissues negatively correlated with overall survival. Treatment with Exo‐TMs up‐regulated the expression of PD‐L1 in macrophages in vitro and in vivo. Bioinformatics analysis suggests that miR‐23a‐3p regulates PD‐L1 expression through the phosphatase and tensin homolog (PTEN)–phosphatidylinositol 3‐kinase–protein kinase B (AKT) pathway. This notion was confirmed by in vitro transfection and coculture experiments, which revealed that miR‐23a‐3p inhibited PTEN expression and subsequently elevated phosphorylated AKT and PD‐L1 expression in macrophages. Finally, coculture of T cells with Exo‐TM–stimulated macrophages decreased CD8+ T‐cell ratio and interleukin‐2 production but increased T‐cell apoptosis in vitro. Conclusion: ER‐stressed HCC cells release exosomes to up‐regulate PD‐L1 expression in macrophages, which subsequently inhibits T‐cell function through an exosome miR‐23a–PTEN–AKT pathway. Our findings provide insight into the mechanism how tumor cells escape from antitumor immunity.

More effective strategies are required to strengthen public awareness of COVID-19: Evidence from Google Trends Background The outbreak of coronavirus disease 2019 (COVID-19) has posed stress on the health and well-being of both Chinese people and the public worldwide. Global public interest in this new issue largely reflects people' s attention to COVID-19 and their willingness to take precautionary actions. This study aimed to examine global public awareness of COVID-19 using Google Trends.Methods Using Google Trends, we retrieved public query data for terms of "2019-nCoV + SARS-CoV-2 + novel coronavirus + new coronavirus + COVID-19 + Corona Virus Disease 2019" between the 31 st December 2019 and the 24 th February 2020 in six major English-speaking countries, including the USA, the UK, Canada, Ireland, Australia, and New Zealand. Dynamic series analysis demonstrates the overall change trend of relative search volume (RSV) for the topic on COVID-19. We compared the top-ranking related queries and sub-regions distribution of RSV about COVID-19 across different countries. The correlation between daily search volumes on the topic related to COVID-19 and the daily number of people infected with SARS-CoV-2 was analyzed. ResultsThe overall search trend of RSV regarding COVID-19 increased during the early period of observing time and reached the first apex on 31 st January 2020. A shorter response time and a longer duration of public attention to COVID-19 was observed in public from the USA, the UK, Australia, and Canada, than that in Ireland and New Zealand. A slightly positive correlation between daily RSV about COVID-19 and the daily number of confirmed cases was observed (P < 0.05). People across countries presented a various interest to the RSV on COVID-19, and public awareness of COVID-19 was different in various sub-regions within countries. ConclusionsThe results suggest that public response time to COVID-19 was different across countries, and the overall duration of public attention was short. The current study reminds us that governments should strengthen the publicity of COVID-19 nationally, strengthen the public' s vigilance and sensitivity to COVID-19, inform public the importance of protecting themselves with enough precautionary measures, and finally control the spread of COVID-19 globally.

Immunosuppression is a significant factor in the progression of tumor invasion and metastasis. Melatonin, a well-known hormone, has certain cytotoxic and immune regulatory effects to inhibit tumor function. Exosomes are small membrane vesicles released by many kinds of cells, which contain different macromolecules, such as mRNAs and microRNAs (miRNAs), and proteins that can mediate communications between cells. Tumor-derived exosomes may cause immunosuppression, however, it is unknown whether melatonin can attenuate an immunosuppressive status by altering the function of tumor-derived exosomes. In the present study, we evaluated the effects of hepatocellularcarcinoma-derived exosomes (Exo-con) and exosomes derived from hepatocellularcarcinoma cells treated with 0.1 mM melatonin (Exo-MT), on the expression of inflammatory factors and programmed death ligand 1(PD-L1) by co-culturing Exo-con and Exo-MT, respectively, with macrophages differentiated from THP-1 cells or RAW264.7 cells. Our in vitro results indicate that Exo-MT can downregulate the expression of PD-L1 on macrophages while Exo-con can upregulate the expression of PD-L1 through flow cytometry and immunofluorescence analysis. In addition, Exo-con upregulates the secretion of cytokines, such as IL-6, IL-10, IL-1β, and TNF-α in macrophages. Accordingly, Exo-MT could attenuate the high expression of these inflammatory cytokines. Furthermore, in vivo experiments confirmed the results found in vitro. PD-L1 expression and cytokine secretion were lower in the Exo-MT group compared with those in the Exo-con group. Working to identify a specific mechanism, our research shows that Exo-MT decreases STAT3 activation compared to the Exo-con group. In summary, we found exosomes from melatonin treated hepatocellularcarcinoma cells alters the immunosupression status through STAT3 pathway in macrophages. Our study may provide a new avenue to investigate the mechanisms of melatonin in regulating an immunosuppressive status.

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Autophagy is a highly conservative cell behavior to keep the intracellular homeostasis and is frequently activated when cells encounter disgusting conditions, such as nutrition or growth factor deprive, hypoxia and cytotoxic agents. However, the precise role of autophagy under various conditions may be opposite, differ from protect cells survival to promote cells death, and the mechanism of this conditional-dependent role is still unclear. Anti-angiogenesis agents, such as bevacizumab, sorafenib and sunitinib, could reduce tumor microvascular density and increase tumor hypoxia, thus up-regulating autophagy activation of tumor cells, but the function of autophagy induced by anti-angiogenesis agents is still divergent and is considered to play a cytoprotective role in most cases. In this review, we mainly discuss the relationship between anti-angiogenesis therapy-induced hypoxia and autophagy, and pay special attention on the exact role of anti-angiogenesis agents induced autophagy in the process of anti-angiogenesis treatment.