Engineering T cell resistance to suppressive cues
The inhibitory tumor microenvironment (TME) impedes the therapeutic benefit of engineered cell therapies. We aim to chart the factors that mediate immunosuppression using loss-of-function genetic screens under suppressive conditions. We test how CRISPR perturbation of genes that mediate suppressive signals can improve T cell function in vitro and in preclinical animal models. Overall, this work will discover key genetic programs that mediate human T cell dysfunction in the inhibitory TME.
Polyclonal anti-tumor immunity by engineered T cells
T cell therapies based on single antigen specificity may lead to tumor escape by antigen-loss or immunoediting. Polyclonal anti-tumor responses may overcome these limitations. We aim to engineer synthetic TCR repertoires in primary human T cells using knock-in of functional TCR sequences to define relationships between T cell specificity and function. This innovative work will reinvigorate anti-tumor responses by engineered polyclonal T cells directed against tumor antigens.
Self-reactive T cells in homeostasis and disease
Immunotherapies that rely on tolerance breakdown often result in immune related adverse events and highlight the high priority unmet need to understand the hidden self-reactive T cell repertoire. We leverage our discovery of genetic factors that tune TCR responsiveness to study pre-existing self-reactive T cells in healthy individuals. We aim to define the role of self-reactivity in humans with implications for autoimmunity and cancer.