Exploring epigenetic regulation of T cell adaptive immunity
Immune cell-based therapies have emerged as a promising new tool in the fight against cancer and chronic infections. Prolonged stimulation of T cells leads to “exhaustion” and limits their ability to function. We use a combination of epigenetic and computational techniques to study this T cell exhaustion. Our laboratory wants to understand the mechanisms that regulate the development of T cells during infection, cancer, and autoimmunity with the goal of improving treatments for these diseases.
Following chronic stimulation, T cells undergo a developmental process known as “exhaustion,” a dysfunctional state reinforced by epigenetic changes that limits their capacity to mount an effector response. The commitment of T cells to this exhausted fate is currently a major barrier in the advancement of T cell immunotherapy efforts. Our lab discovered that T cells can resist exhaustion when a particular enzyme is knocked out – even if the source of antigen persists. We are now applying this perturbation approach to CAR T cells, creating persistent populations of functional cells that we can now evaluate in clinical trials at St. Jude.
Our laboratory employs cutting-edge epigenetic and transcriptional profiling techniques, gene engineering approaches in human and murine models of T cell exhaustion, and computational analyses to identify molecular mechanisms of T cell exhaustion. We then work to develop innovative strategies to block exhaustion and prolong T cell responses during immunotherapy. This work not only provides insight into the process of T cell exhaustion, but also reveals clues to improve T cell-based immunotherapies.
We are actively extending our research toward immuno-oncology, specifically the tumor microenvironment’s role in T cell differentiation and how we can leverage our previous discoveries to better understand tumor immunology.