# Targeting the suppressive immune microenvironment in leptomeningeal melanoma metastases

> **NIH NIH R21** · H. LEE MOFFITT CANCER CTR & RES INST · 2022 · $188,644

## Abstract

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.

## Key facts

- **NIH application ID:** 10456946
- **Project number:** 5R21CA256289-02
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Keiran Smalley
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $188,644
- **Award type:** 5
- **Project period:** 2021-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456946

## Citation

> US National Institutes of Health, RePORTER application 10456946, Targeting the suppressive immune microenvironment in leptomeningeal melanoma metastases (5R21CA256289-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10456946. Licensed CC0.

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