Anti-PD-1/PD-L1 therapy is a promising approach in cancer therapy. We showed that glycosylation of PD-L1 is required for its protein stability and interaction with PD-1 (Nature Communications 2016). We demonstrated TNFα as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1) (Cancer Cell2016). In collaboration with StCube Pharmaceuticals Inc., we have developed monoclonal antibodies against glycosylation-specific PD-L1. Impressive therapeutic effect was observed through antibody-drug-conjugate approach (Cancer Cell 2018a & Cancer Res 2020). Furthermore, we developed effective combination therapy by metformin-activated AMPK kinase to downregulates PD-L1 through alteration of glycosylation of PD-L1 and (Molecular Cell 2018). Our group has conducted a series of vigorous studies to identify additional potential targets to overcome PD-1/PD-L1 resistance and develop effective combination therapy including c-MET inhibitors (Gastroenterology2019), IL-6/JAK1 pathway (J Clin Invest 2019), and Galectin-9 (Nature Comm 2021). These findings provide potential therapeutic strategies to enhance cancer immune therapy efficacy by targeting PD-L1 stabilization to combat multiple cancer types. We reported a novel PD-L1 function that is independent of its role in immune checkpoint in Nature Cell Biology 2020--PD-L1 in the nucleus harbors a nuclear transcriptional activity and promotes tumor pyroptosis downstream of TNFα. More recently, we further identified molecular mechanisms that caused resistance to anti-PD-1/PD-L1 therapy (J Clin Invest, 2021) and currently are developing new therapeutic approach to overcome the resistance. This talk will include our discoveries on developing therapies for lung or pancreatic cancers (Cancer Cell2018b, 2018c); a new methodology to retrieve antigen by protein deglycosylaton improves predictive ability of PD-L1 as a biomarker for immunotherapy. (Cancer Cell2019, AJCR 2022). I will also summarize multiple new advances of anti-PD-L1/ PD-1 that have recently been developed in the literature (Nature Reviews Clinical Oncology, 2022). In addition, we identified the inhibition of the protein kinase activity of PCK1 as a potential treatment strategy in HCC (Nature 2020) and currently developed high throughput screening strategy to identify potential inhibitors for treatment.
During the pandemic, the research team at China Medical University in Taichung has successfully used our experience and expertise in cancer targeted therapy to target SARS-CoV-2. In this talk I will briefly summarize our results from screened multiple natural products libraries. (AJCR 2020,2021; JBC 2022, in press). For instance, both tannic acid and peimine have inhibitory effects on SARS-CoV2 infection. Tannic acid is a bioactive compound that can be found in berries and grapes, and peimine is an active ingredient of Chuan Bei. We found that tannic acid serves as a potent dual inhibitor of viral main protease Mpro and TMRPRSS2 protease on the host cells, and peimine inhibits several variants of SARS-CoV-2 cell entry via blocking the interaction between viral spike (S) protein and ACE2 on the host cells, respectively. The goal is to identify natural products that may help for prevention and therapy of Covid-19 through inhibition of SARS-CoV-2.
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