Development of an MRI gene and application to probing the tumor microenvironment

Northwestern University, Evanston IL

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Abstract

DESCRIPTION (provided by applicant): The relationship between cancer and the immune system is heavily implicated in the outcome of the disease. Unfortunately few methods exist to monitor the immune microenvironment immediately around the tumor. The goal of this project is to develop a novel magnetic resonance imaging (MRI) based reporter gene and apply it to the field of cancer immunology. This will be accomplished by (1) developing a reporter gene based on the HaloTag protein that can report gene expression with contrast on an MR image and (2) proving its applicability to a simple model organism before (3) finally using it to monitor the presence of Interleukin-10 (IL-10) in vicinity of melanoma tumors. Recent work in the Meade lab has produced a suite of Gd(III) contrast agents that bind tightly to the HaloTag protein and dramatically increase MR signal when bound. Combining these technologies creates the potential to construct an MRI based reporter gene system, whereby the expression of a gene produces a bright spot on an MR image. Such a technology would have innumerable uses, particularly in the fields of developmental biology, cancer, and immunology. Each of these fields would benefit greatly from the unparalleled deep tissue resolution offered by MRI. The MR reporter gene system will be tested in Xenopus laevis, a common model organism used in developmental biology, by placing HaloTag under the control of a promoter active in the vasculature. In order to detect IL-10 in situ a cell-based biosensor will be used that includes a modular extracellular sensory architecture to cause specific gene expression upon binding to IL-10. In the proposed system, the binding of IL-10 will result in expression of exogenous, extracellular HaloTag. Exposure to HaloTag targeted contrast agents will result in MR contrast enhancement specifically in locations of elevated IL-10 concentration. This technique is expected to be generalizable to a wide variety of cytokines, eventually allowing detailed descriptions of tumor-immune system interactions on a local level.