Targeting the suppressive immune microenvironment in leptomeningeal melanoma metastases

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Melanoma is a highly metastatic tumor, with a propensity to spread to the skin, lungs and brain. In ~5% of cases, patients also develop leptomeningeal melanoma metastases (LMM: e.g. melanoma cell infiltration into the pia mater, the arachnoid membranes and cerebrospinal fluid) which has a dismal survival of 8-10 weeks. There are no effective treatments for LMM. Understanding the biology of LMM in the context of drug response/resistance is a major unmet need. In preliminary studies, we used single cell RNA-Seq (scRNA-Seq) to identify a novel population of myeloid cells in samples of CSF from patients with LMM, which we believe suppress adaptive immune responses. We will test the hypothesis that myeloid cells in the LMM microenvironment are critical regulators of tumor progression and therapeutic response, and that the long-term management of LMM will require therapies that target both the melanoma cells and the immune-suppressive signals from the tumor microenvironment (TME). In Aim 1, we will use scRNA-Seq, flow cytometry and immunofluorescence to characterize the immune environment of CSF from patients with LMM, with a focus on the myeloid compartment. Functional studies will be undertaken to 1) determine the role of the CSF environment on myeloid cell differentiation 2) demonstrate that CSF-resident myeloid cells suppress T cell function. We will then interrogate serial CSF samples from our phase Ib clinical trial of patients with LMM to determine how inhibiting PD-L1 and radiation therapy shapes the myeloid and T cell repertoire of the CSF space. In Aim 2, we will define the role of myeloid cells in LMM progression in vivo. We will then perform in vivo experiments using mouse melanoma cells grown in the leptomeninges of C57/BL6 mice to determine if systemic or intrathecal inhibition of CCR2 and/or CSF1R sensitizes LMM to anti PD-1 in syngeneic mouse models of melanoma. We expect to define the immune environment of LMM and to develop the rationale for novel therapeutic strategies that can be rapidly evaluated in this most devastating complication of advanced melanom a.