My research interests lie in discovering the regulatory mechanisms of cancer metastasis and immune resistance in preclinical settings. On the basis of the newly identified signaling pathway(s), I investigated the therapeutic potentials of natural food compounds, small molecular inhibitors, and monoclonal antibodies to reduce cancer progression in the hope of translating these findings from basic research into clinical use. My past and current research has enabled me to work closely with basic scientists, pharmaceutical companies, and clinicians. I would like to continue executing this multidisciplinary collaboration on essential clinical questions in my future endeavor.
My current interest is focused on cancer immunotherapy. The field of immuno-oncology has dramatically reshaped the landscape of cancer therapy since the development of antibodies blocking immune checkpoint proteins, which attenuate anti-tumor immunity by inhibition of T-cell activation (model shown on the right). To date, antibodies targeting immune checkpoint protein PD-1 and PD-L1 have been approved by the FDA to treat 25 types of cancers in over 120,000 patients. Despite their clinical success, issues such as missing targets, intrinsic/acquired resistance, hyperprogressive diseases, the lack of reliable biomarkers, and autoimmune diseases have now become the new challenges awaiting further investigation. My research interest in cancer immunotherapy lies in the understanding of the molecular interaction between cancer and infiltrated T cells in the primary and metastatic tumor microenvironment. Specifically, I sought to understand the post-translational modifications of PD-L1 and their effects on immunosuppression. I found that N-linked glycosylation of PD-L1 on cancer cells prevents its degradation via 26S proteasome and enhances its engagement with PD-1 on the CD8+ T cells (Nature communication 2016, Li et al.). In addition, I subsequently reported that chronic inflammation by TNFα induces PD-L1 stabilization through COP9 signalosome subunit 5 (CSN5)-mediated de-ubiquitination in TNBC (Cancer Cell 2016, Li et al.). The results reported in these two publications suggested that targeting PD-L1 glycosylation, phosphorylation, or ubiquitination may be a potential strategy to enhance anti-tumor immunity. Most recently, I found that glycosylation of PD-L1 is required for PD-1 interaction through beta-1,3-N-Acetylglucosaminyltransferase 3 (B3GNT3)-mediated GlcNAc-β-1,3-Gal (LacNAc) glycosylation (Cancer Cell 2018, Li et al.). In collaboration with STCube Pharmaceuticals, we further generated a first-in-class anti-glycosylated PD-L1 antibody (gPD-L1 mAb) (Patents 2015) and showed that this novel antibody induces PD-L1 internalization for lysosomal degradation. Moreover, we also generated an antibody-drug conjugate (ADC) of gPD-L1 which can provide an extra benefit by eradicating the surrounding cancer cells with little or no PD-L1 expression (Cancer Cell 2018, Li et al.).