Research in Wu’s lab focuses on:
Mechanisms of Cancer Immune Evasion and Development of Novel Cancer Immunotherapy
This area has been the major focus of my laboratory during the last decade. In response to oncogenic insults (DNA damage, oxidative stress, or viral infection), human tumor cells were induced to express a class of MHC I chain (MIC) like molecules on the surface to signal and activate the immune system. Ideally, this immune activation is to control tumor growth. However, in cancer patients, malignant tumor cells shed the surface MIC to produce soluble MIC (sMIC). Studies have shown that sMIC may confer immune suppressive effect through multiple pathways such as impairing NK and CD8 T cell function and facilitating expansion of MDSCs in tumor microenvironment.
Clinically it has shown that cancer patients with high levels of serum sMIC had poor response to immune checkpoint blockade therapy. These understandings endow sMIC to be potential therapeutic target. However, due to the fact that MIC is a human molecule and that no MIC homolog is found in rodents, the therapeutic proof-of-concept could not be achieved until we generated the state-of-the art MIC-transgenic mouse models. With these models, we have shown that anti-sMIC therapy invigorates NK and antigen-specific CD8 T cell anti-tumor responses. Our current focus is to understand the mechanism whereby the ant-sMIC therapy stimulates NK and antigen-specific CD8 T cell responses. These fundamental understandings will have board implications on how to enhance current approved and in-development immunotherapies, including immune checkpoint blockade (ICB) therapy, cell-based therapy, and vaccine therapies.
Understanding Immunotherapy-induced Toxicity
Colitis is the most severe toxic effect of current ICB therapy of cancer. There is no mechanistic-guided management of ICB-induced colon toxicity. Current clinical management of ICB-induced colitis is borrowed from classic IBD management. However, this approach is often insufficient or causes complications. Frequently, therapy has to be stopped in patients. With the access to clinical samples and our unique preclinical models of ICB-induced colitis (Zhang et cl., 2017 Science Advances), we are addressing the mechanisms of ICB-induced colitis in order to develop an effective clinical management strategy.
Cancer Biomarker Discovery
Prostate specific antigen (PSA) screening is an established and useful tool for prostate cancer detection, however, it has no predictive prognostic value at diagnosis. For early diagnosed localized prostate cancer, the major clinical challenge is the treatment decision, in whether a patient should receive invasive intervention or be managed as “watchful waiting” active surveillance. Consequently, patients with indolent prostate cancer can be unnecessarily over-treated; or conversely, patients with prostate cancer of an aggressive nature may miss out on needed treatment, which ultimately leads to mortality. Therefore, it is an urgent need to develop prognostic biomarkers for localized prostate cancer to guide clinical decision making that is most beneficial to each patient. In collaboration with Dr. Drake’s lab at MUSC, we are addressing the imminent clinical need by developing and validating a panel of potential prostate cancer prognostic biomarkers.