Our Research
Our research focuses on understanding the molecular mechanisms underlying T cell dysfunction in immune-related diseases. We are developing novel therapies by engineering immune cells and targeting key pathways involved in disease progression.
Project 1: T Cell Lymphoma
Through extensive genomic analysis of a growing cohort of patients, we have identified key genetic drivers of T cell lymphomas. Our findings have revealed novel mutations in genes involved in T cell receptor signaling, including the first reported gain-of-function mutations in CD28, RLTPR and CSNK1A1. These mutations enhance T cell receptor signaling without completely replacing its function.
Unexpectedly, we discovered that many T cell lymphomas exhibit features of T cell exhaustion, despite our initial prediction of hyper-responsiveness to antigens. However, a subset of lymphomas with inactivating mutations in PD1 showed enhanced proliferation in vitro and poorer clinical outcomes in vivo. These PD1-mutant lymphomas are characterized by increased PI3K-dependent anabolism and altered epigenetic modifications. These findings are summarized in manuscripts at Nature Genetics, Nature Communications, Cell Reports, Blood and Nature Cancer.
Our goal is to better understand molecular mechanisms, validate the biomarker across a larger, multi-institutional cohort and to develop novel therapies.
Project 2: T Cell Engineering
Our lab has harnessed our understanding of T cell biology to develop novel strategies that enhance the efficacy and persistence of adoptive T cell therapies, including chimeric antigen receptor-T and T cell receptor-T cells. These results are summarized in a manuscript in press at Nature.
Project 3: Curing Autoimmune Disease
In collaboration with Deepak Rao, MD, PhD, at Brigham, we are investigating the molecular mechanisms underlying pathogenic T cells in autoimmune diseases like systemic lupus erythematosus. Using CRISPR screening and epigenetic approaches, we have identified key transcriptional drivers of T peripheral helper cells and explored strategies for reprogramming these cells. Our findings, to be published in Nature, may lead to novel therapeutic interventions for autoimmune diseases.
Project 4: Precision Medicine
To develop personalized treatment approaches, we are analyzing the immune cell composition of tumor and autoimmune microenvironments using single-cell RNA-sequencing and spatial transcriptomics. Our goal is to identify specific molecular pathways involved in disease progression and drug resistance, which may lead to the discovery of targeted therapies.