The goal of this application is to develop and validate a novel noninvasive metabolic imaging approach that informs on arginine metabolism as a readout of the immunosuppressive pro-tumoral activity of myeloid-derived suppressor cells (MDSCs), and the inhibition of this activity by immunotherapeutic treatment in glioblastoma (GBM). Tumors use a variety of mechanisms to escape the host immune system, and many of these mechanisms are being targeted by immunotherapy. One of the main mechanisms is associated with elevated tumoral levels of aberrant myeloid cells called MDSCs. MDSCs produce and secrete into the extracellular space elevated levels of the enzyme arginase, which converts arginine into urea and ornithine. Additionally, some MDSCs also overexpress the arginine transporter and the inducible nitric oxide synthase (iNOS) enzyme. Together, arginase and iNOS lead to depletion of arginine in the tumor microenvironment. Importantly, arginine is essential for T-cell proliferation, therefore depletion of arginine results in inhibition of T-cell function, and thus immune evasion and uninhibited tumor growth. Importantly, MDSCs represent as much as 40% of the brain tumor mass. MDSC-associated metabolism is therefore likely to be detectable by magnetic resonance spectroscopy (MRS). Our preliminary data indicate that using 13C MRS we are able to probe the metabolism of hyperpolarized 13C-guanido-arginine by arginase at enzyme concentrations that are lower than those observed within a brain tumor. We therefore hypothesize that hyperpolarized 13C-guanido-arginine can serve as a 13C MRS imaging probe for arginase and iNOS in brain tumors and, as such, could inform on 1. the pro- tumoral activity of MDSCs and 2. the inhibition of this activity by MDSC-targeting immunotherapies. We will test this hypothesis via the following aims.
Aim 1. To confirm hyperpolarized 13C-guanido-arginine as a metabolic imaging probe for detection of intracellular and extracellular arginine metabolism by MDSCs. We will investigate MDSCs from multiple mouse strains and use 13C MRS to probe the intracellular and extracellular metabolism of hyperpolarized 13C-guanido-arginine. We will determine if hyperpolarized arginine metabolism is associated with intracellular and extracellular arginase and iNOS activities.
Aim 2. To validate hyperpolarized 13C-guanido-arginine as a method for imaging MDSCs and their inhibition by MDSC-targeted immunotherapy in GBM models in vivo. We will use 13C MRS to probe the fate of hyperpolarized 13C-guanido-arginine in control and immunotherapy- treated mice with syngeneic tumors, and determine if changes in arginine metabolism correspond with tumoral MDSC infiltration, tumoral enzyme activities, and the modulation of these factors by immunotherapy.
The proposed research will address the currently unmet need for a noninvasive imaging method to monitor the presence of tumoral MDSCs and their immunosuppressive pro-tumoral activity, as well as the efficacy of MDSC-targeting immunotherapies in GBM. This innovative imaging approach will provide an important tool to further understand the role of MDSCs in tumor development, and to assess the efficacy of emerging immunotherapies. Beyond this study, our approach could also be used more broadly for imaging neuroinflammatory diseases of the brain.
|Najac, Chloé; Chaumeil, Myriam M; Kohanbash, Gary et al. (2016) Detection of inflammatory cell function using (13)C magnetic resonance spectroscopy of hyperpolarized [6-(13)C]-arginine. Sci Rep 6:31397|
|Najac, Chloé; Ronen, Sabrina M (2016) MR Molecular Imaging of Brain Cancer Metabolism Using Hyperpolarized 13C Magnetic Resonance Spectroscopy. Top Magn Reson Imaging 25:187-196|
|Viswanath, Pavithra; Najac, Chloe; Izquierdo-Garcia, Jose L et al. (2016) Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters. Oncotarget 7:34942-55|