Abstract
Myeloid-derived suppressor cells (MDSCs) are highly prevalent inflammatory cells that play a key role in tumor development and are considered therapeutic targets. MDSCs promote tumor growth by blocking T-cell-mediated anti-tumoral immune response through depletion of arginine that is essential for T-cell proliferation. To deplete arginine, MDSCs express high levels of arginase, which catalyzes the breakdown of arginine into urea and ornithine. Here, we developed a new hyperpolarized 13C probe, [6-13C]-arginine, to image arginase activity. We show that [6-13C]-arginine can be hyperpolarized, and hyperpolarized [13C]-urea production from [6-13C]-arginine is linearly correlated with arginase concentration in vitro. Furthermore we show that we can detect a statistically significant increase in hyperpolarized [13C]-urea production in MDSCs when compared to control bone marrow cells. This increase was associated with an increase in intracellular arginase concentration detected using a spectrophotometric assay. Hyperpolarized [6-13C]-arginine could therefore serve to image tumoral MDSC function and more broadly M2-like macrophages.
Highlights
Arginine metabolism could serve as a readout of myeloid-derived suppressor cells (MDSCs) activity and as a method to detect the inhibition of this activity in response to MDSC-targeted treatment
To validate the hypothesis that hyperpolarized [6-13C]-arginine can serve as an imaging probe for MDSC activity and function, we first determined the enhancement in polarization that can be achieved for this new probe, and its longitudinal relaxation time T1
We examined arginine metabolism using 13C MRS and hyperpolarized [6-13C]-arginine in MDSCs generated by culturing bone marrow cells with IL-13 and in control BM cells cultured without IL-13
Summary
Arginine metabolism could serve as a readout of MDSC activity and as a method to detect the inhibition of this activity in response to MDSC-targeted treatment. One study, performed in a model of murine breast carcinoma, detected MDSCs in vivo using perfluorocarbon (PFC)-based 19F MRI28. This approach is unable to probe cell function. The most common probe, hyperpolarized [1-13C]-pyruvate, has been widely used in cell and animal models of cancer, wherein elevated production of hyperpolarized [1-13C]-lactate can serve to detect the presence of tumor cells, and a drop in hyperpolarized [1-13C]-lactate is associated with response to treatment[30,37,38,39,40]. Lactate up-regulation from inflammatory cells and tumor cells are indistinguishable, limiting the utility of hyperpolarized [1-13C]-pyruvate as a specific probe for the detection of MDSCs in cancer. We demonstrate that we can detect hyperpolarized [13C]-urea production from hyperpolarized [6-13C]-arginine in activated MDSCs but not in control bone marrow (BM) cells, confirming the utility of hyperpolarized [6-13C]-arginine as a probe for monitoring ARG expression in cells
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