The Sen laboratory investigates the regulation of T cell dysfunction and explores epigenetic approaches for T cell engineering. We have found that the regulatory “circuitry” of dysfunctional T cells differs remarkably from functional T cells fighting off acute infections. By comparing chronic viral infections and cancer, we showed that this altered epigenetic wiring is a fundamental adaptation to chronic diseases and cannot be rescued by current treatments. Therefore, improved mechanistic understanding of this altered regulation will be critically important for reversing immune dysfunction. The fundamental questions we try to answer through our work in the lab are:

How do T cells commit to exhaustion? T cell exhaustion, like many cellular differentiation processes, develops with a continuum of phenotypic and functional intermediate states. We are exploring how these early regulatory changes initiate an exhausted epigenetic state that eventually becomes fixed and mediates downstream functional deficits.

How does the disease-specific microenvironment shape T cell dysfunction? Major questions remain about the impact of dysfunctional T cells and the specific tumor/infection contexts in which they arise. We are now defining context-dependent differences that are induced by different cell-cell interactions, treatment regimens etc. and defining new mechanisms that affect T cell effector function.

How can we rescue dysfunctional T cells? Our previous work suggests that many current therapeutic modalities, such as PD-1 checkpoint blockade in tumors or curative therapy in chronic infection, cannot reverse the epigenetic changes associated with exhaustion. Therefore, the most successful strategies to address T cell dysfunction must prevent the early establishment of this program. The Sen lab is taking functional genomics and epigenomics approaches to reprogram dysfunctional T cells.