CD8 T lymphocytes are our most important defense against tumors or virus-infected cells. When a naive CD8 T cell encounters its specific antigen within proper inflammatory microenvironment, it undergoes clonal expansion and differentiates into highly cytotoxic effector cells that quickly eradicate virus-infected cells during acute infections (e.g., influenza, measles, yellow fever). Most of these cytotoxic T cells die afterwards, while a minor population of T cells survive and differentiate into memory T cells that provide long-term protection against many previously encountered acute pathogens. Such long-term (or lifelong) protection requires the capacity of T cells to self-renew while maintaining a memory of their cytotoxic program.
On the other hand, cytotoxic T cells progressively lose their effector function and become “exhausted” during chronic infections or cancer. T cell exhaustion remains a major challenge to T cell immunotherapy. Recently, this barrier was somewhat surmounted with the advent of immune checkpoint blockade (*ICB) therapy that can rejuvenate partially exhausted T cells by blocking their surface inhibitory receptor signaling (e.g., CTLA-4, PD-1/PD-L1). Despite the unprecedented success of ICB therapy in treating multiple previously refractory cancers, many patients remain nonresponsive while some patients relapse after initial clinical response.
Epigenetic programming regulates gene expression and cell fate commitment via alterations in the chromatin landscape, including covalent modifications to DNA and histone proteins. We were the first to show that de novo DNA methylation programs are causally linked to T cell silencing, and enforce full exhaustion during chronic virus infection and cancer. More importantly, we discovered that these T cell-intrinsic epigenetic programs restrain the efficacy of ICB therapy (Ghoneim, et al. Cell 2017).
Our lab aims to understand how T cell immune responses are generated and maintained during infections and cancer. We are particularly interested in:
1- Elucidating the mechanisms of epigenetic programming in CD8 T cells during infections and cancer.
2- Understanding how de novo epigenetic programs are regulated during the development of T cell exhaustion
3- Discovery of novel therapeutic targets to epigenetically reprogram T cells for treating chronic virus infections and cancer.