Our research program is focused on delineating the role of non-coding RNAs in T cell differentiation. Our vision is to uncover the role of non-coding RNAs in regulating T cell responses to infection and cancer and develop novel immunotherapy strategies using non-coding RNAs. Since my early postdoctoral studies, I have been intrigued by the role of microRNAs in the immune system. MicroRNAs have the potential to target hundreds of mRNAs simultaneously; therefore, affect key cellular, molecular and epigenetic pathways and regulate immune responses. However, the role of microRNAs in regulating T cell differentiation and tuning responses to immunotherapy is understudied.

CD8 T cell responses are the hallmark of immune responses to viral infections and cancer. Transcriptional and epigenetic pathways regulate CD8 T cell responses, however the role of non-coding RNAs has not been elucidated. Using microRNA profiling in CD8 T cells, we predicted that three microRNAs, miR-150, miR-155, and miR-29 may regulate CD8 T cell responses to viral infections and cancer. Indeed, we first demonstrated that miR-155 is a crucial regulator of effector CD8 T cell responses, while miR-150 regulates memory CD8 T cells by targeting c-Myb. We further extended these studies in microRNAs regulating CD8 T cell exhaustion and responses to chronic infection and cancer. Thus, we identified a key role for miR-155 to sustain the persistence of exhausted cells, by fostering the durability of terminally exhausted cells. Recently, we identified miR-29a as a memory-promoting microRNA that enhances CD8 T cell responses to chronic infection and cancer and improves the phenotype and function of exhausted cells. Collectively, these studies suggest that microRNAs are key players in antiviral and anti-tumor CD8 T cell responses and that modulating the expression of miR-29a has the potential to improve immunotherapy.

Our ongoing and future studies are focused on uncovering the molecular, transcriptional and epigenetic circuits governed by microRNAs that instruct T cell differentiation and exploring novel strategies to deliver microRNAs in order to improve responses to immunotherapy.