Contribution of Myeloid-Derived Suppressor Cells to Neuro-Inflammatory Alterations and Disease Progression in Glioblastoma

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ABSTRACT: Glioblastoma (GBM), the most common primary brain tumor, remains uniformly lethal due to many factors, including a potently immune-suppressive microenvironment. While attempts to alter immune activation have been successful in other advanced cancers, a series of diverse strategies has yet to markedly increase GBM patient survival. These results demonstrate a key clinical barrier to success and underscore the need to better understand the immune-suppressive GBM microenvironment, which is part of a unique neuroimmune system. Central to immune suppression in GBM is the presence of myeloid-derived suppressor cells (MDSCs), an immature lineage comprised of monocytic (m) and granulocytic (g) subsets that potently suppresses cytotoxic immune response. Interrogating the function of MDSCs in GBM has been a major focus of our laboratory. Using an integrated approach, we have shown that MDSCs associate with poor GBM prognosis, drive cancer stem cell function, and interact with the tumor through multiple signaling networks that can be neutralized to increase immune activation. We have also interrogated MDSC subsets to reveal differences in localization and function in a sex-specific manner and identified MDSC subset signaling programs that can be altered to increase immune activation and decrease GBM growth. While our work has implicated MDSCs as biomarkers and drivers of GBM progression and identified them as next-generation therapeutic targets, there are several knowledge gaps that remain, and addressing them is the focus of this application: it remains unclear how MDSCs originate and the extent of their plasticity; it is unclear how MDSC lineage commitment is informed by cell-intrinsic programs and is altered as a result of interaction with unique neural microenvironments, microbial interactions, and signaling programs; and the efficacy of targeting MDSC subsets in combination with immune activating strategies has yet to be determined. The overarching hypothesis of this application is that MDSC subset lineage commitment is driven though the integration of cell-intrinsic (including sex-specific genetic and epigenetic programs) and cell- extrinsic (including systemic factors from the gut-brain axis) interactions that can be leveraged for the development of more effective anti-GBM therapies. Through this R35 mechanism that allows for longer- term/flexible funding to develop parallel areas with synergistic potential, we will test distinct aspects of this hypothesis though three complementary but integrated focus areas: (1) the cellular and molecular basis for MDSC lineage commitment and plasticity, (2) the response of MDSCs to microenvironmental cues, and (3) pre- clinical MDSC targeting in combination with immune activating therapies. These studies have immediate implications for GBM and other neurological disorders and establish a platform for understanding immune responses in other neurological disorders by providing unique insights into neural/immune interactions mediated via MDSCs, as well as by assessing brain-penetrant immune-altering therapeutic strategies.