Research in the Riese lab focuses on understanding how T cells are affected by the tumor microenvironment, and how they can be manipulated to overcome the inhibitory mediators present within that environment.
One means to enhance T cell responses is to target negative modulators of signal transduction downstream from the T cell receptor (TCR). Perhaps the most important signaling event downstream of the TCR is the cleavage of the phosphoinositide PIP2 into the second messengers diacylglycerol (DAG) and IP3. Whereas IP3 mobilizes Calcium flux from the endoplasmic reticulum, DAG binds and activates additional proteins important in signal transduction, such as the Ras activating protein RasGRP1. DAG-mediated signaling is terminated by diacylglycerol kinases (dgk’s), which phosphorylate DAG to form phosphatidic acid. It has been appreciated for some time that inhibition of dgk’s results in enhanced TCR signal transduction and imparts enhanced function to T cells. We have found that T cells deficient in dgk’s generate enhanced anti-tumor responses in a variety of murine models. A major focus of the lab is to dissect the molecular underpinnings of how dgk’s function to limit anti-tumor responses.
Chimeric antigen receptors (CARs) represent an emerging strategy for generating T cell responses against tumors. CARs are fusion proteins that contain an extracellular antibody domain specific for a given tumor antigen linked to an intracellular T cell signaling component, such as CD3ζ. CD8+ T cells can be engineered to express CARs such that contact with tumor cells and their cognate antigens results in T cell activation and cytolysis of tumor cells. A second major focus of the lab is in understanding how CARs utilize TCR machinery to transduce signals and how these signals can be optimized to enhance tumor cell lysis.
Vidhya Arumugam, Ph.D.
Asst. Research Technologist
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