Krenciute Lab

Our lab has long been interested in identifying the antigen signatures of pediatric brain tumors to guide the development of CAR T cells. We set out to determine the unique landscape of these tumors and identify differences from the adult disease. Our experiments have defined a hierarchy of tumor specific antigens quite distinct from adults, for which we have engineered and evaluated specific CAR T cells. We use in vitro and in vivo techniques to determine the efficacy of these CAR Ts, creating small iterations in signaling domains to optimize function. We are still exploring possible candidates, and plan to incorporate large scale screening and -omics based approaches to further define the landscape of tumor associated antigens. Much of this work is conducted in close collaboration with the pediatric brain tumor experts Drs. Martine Roussel and Suzy Baker.

We also apply genetic manipulations to optimize CAR T cells, with a particular focus on negative regulators of immune cell function. By knocking out these negative regulators, and investigating the resulting biology, we can improve T cell anti-tumor activity and persistence. In many cases, we know what regulators, genetic or epigenetic, control T cell function, and so we work to explore the mechanisms by which they impact CAR T cell biology and activity.

Understanding the resulting CAR T cell phenotypes, genetic and epigenetic signatures will lead to additional lines of investigation as we work to optimize CAR T cell functionality. Much of this work is conducted in close collaboration with Dr. Ben Youngblood, an expert on T cell epigenetics, and other principal investigators in the Department of Immunology.  

In the course of our work, we observed that engineered CAR T cells were not always effective at irradicating a tumor despite robust expression of a particular antigen. As a result, our lab has started exploring the interactions between CAR T cells, tumor cells and the tumor microenvironment. We are interested in determining whether physical properties of the tumor, or immune landscape of the surrounding environment, impact CAR T cell function.