TMIC-87. CXCL1-CXCR2 Signaling Mediates Leptomeningeal Metastasis Progression

Leptomeningeal metastasis (LM) describes the spread of cancer into the cerebrospinal fluid (CSF) filled leptomeningeal space surrounding the brain and the spinal cord. Historically, LM is described as neoplastic meningitis, reflecting the inflammatory characteristics of the disease. Cancer infiltration into the CSF triggers the influx of leukocytes, elevation of inflammatory cytokines, and breakdown of blood-CSF barrier. To identify key mediator of cancer progression in LM induced inflammation, we performed proteomic analyses on serially collected CSF from patients in recent clinical trial. Elevated CXCL1 levels were observed in LM positive patients, and higher CSF CXCL1 levels correlate with poor progression-free survival. Using syngeneic mouse models of LM, we confirmed the expression of Cxcl1 in both cancer and host cells, including macrophages, choroid plexus epithelial cells and meningeal fibroblasts. After engraftment into the host, cancer cells dynamically modulate the Cxcl1-Cxcr2 inflammatory axis, reflexing their interaction with tumor microenvironment. To investigate the functional role of tumor and host Cxcl1, we selectively deleted Cxcl1 in both the cancer cells and host cell populations. We find that cancer cell generated Cxcl1 is essential for cancer progression while host derived Cxcl1 is dispensable. Additionally, we find that pharmacological inhibition of Cxcr2 enhances cancer sensitivity to radiation therapy. Together, these findings demonstrate that the CXCL1-CXCR2 signaling axis acts as a critical mediator of LM progression, and suggests that this signaling axis may serve as an appealing therapeutic target for this fatal complication of cancer.