Our lab aims to harness a critical group of innate T cells, NKT cells for anti-cancer and anti-anti-viral therapies. NKT cells are an unconventional subset of T cells co-expressing T-cell receptor (TCR) and typical surface receptors for NK cells. In contrast to conventional adaptive T cells and B cells, NKT cells have features of both innate and adaptive arms of immune systems. Over the last several decades, NKT cells have been found to influence diverse immune responses, including immunity to infectious diseases and tumor, autoimmune diseases and allergies. The major group of NKT cells express identical or similar T cell receptors and are often called invariant NKT cells or iNKT cells. During immune responses, NKT cells are rapidly activated to produce cytokines such as g-interferon (IFN-g) and IL-4, and their activation plays a key role in the development and regulation of adaptive immune responses to microbes.
Due to the critical antiviral roles of NKT cells, herpes viruses have evolved strategies to antagonize this function. We are particularly interested in how these prevalent and latent viruses overcome the function of NKT cell function and establish infection in humans (Yuan, W. et al., Nature Immunol. 2006, 7, 835-842). Remarkably, we identified a HSV-1 protein kinase, US3, potently down-regulates CD1d expression in antigen presenting cells and suppresses the function of the essential cellular motor protein, kinesin to block CD1d expression (Rao, P. et al., J. Virol. 2011, 85: 8093-8104; Ran, X. et al., J. Virol. 2015, 89: 6646-6655). Currently we are pursuing how US3, through its kinase activity, modulates CD1d recycling pathway at both molecular and cellular levels. In the long run, to break down the viral immune evasion mechanism will help to improve the immunogenicity and therefore the protection efficiency of vaccine candidates to prevent new herpesvirus infections.
An emerging research field in my lab is to explore the potent immunoregulatory function of human NKT cells for anti-cancer therapies. Despite a high degree of conservation, substantial differences exist between the CD1d antigen presentation pathways and NKT cell populations in humans and mice. These differences mostly account for the suboptimal success of natural killer T (NKT) cell-based antitumor therapies so far in human clinical trials. In order to study human-specific CD1d antigen presentation pathway in vivo, we have pioneered in humanizing the CD1d/NKT system in mice (Wen, X., et al., Proc. Natl. Acad. Sci. USA 2013, 110: 2963-2968; Wen, X., et al., J. Immunol. 2015, 195: 1459-1469) (See Figure). We have employed these novel mouse models to identify potent glycolipids that working efficiently in human CD1d/NKT cell system. We look forward to translating these results to human clinics and explore more human CD1d and human iNKT TCR-based therapies. Our long-term goal is to combine these NKT cell-based immunotherapies with current first-line immunotherapy regimes to optimize the treatment efficacy and overcome the limitations of current immunotherapies.