Our laboratory, based at the Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT, studies the mechanisms that regulate T cell function in humans. We use a range of approaches including cellular immunology, functional genomics, epigenetics, and single cell profiling to understand why protective T cell memory fails to occur in cancer and chronic viral infection.
Some of the ongoing projects in our lab include:
- Single cell analysis of functional and exhausted T cells in tumors and chronic viral infections from humans and mouse models. These projects aim to discover new subtypes of exhausted T cells and the genes that regulate them.
- Transcriptional regulation of T cell exhaustion. We use assays of chromatin accessibility, histone modifications, and transcription factor binding to understand how gene expression is regulated in T cell differentiation and how it goes wrong in T cell exhaustion.
- Genome editing of T cells. We have developed a novel approach that allows inducible genome editing in vivo to identify new genes and explore the function of regulatory regions that control T cell differentiation.
- Immunotherapy target discovery. Using a new experimental system, we are conducting pooled genome-scale Cas9-mediated loss-of-function screens in mouse tumor models. These screens aim to identify genes that confer resistance to immune checkpoint blockade and new targets for cancer immunotherapy. In complementary studies, we are also using pooled gain-of-function screens to identify oncogenes and mutant alleles that enable immune evasion.