Immune remodeling and myeloid signature in the bone marrow niche of MYCN-driven neuroblastoma.

Abstract

Background: High-risk MYCN-amplified neuroblastoma is associated with a dire prognosis and often metastasizes to the bone marrow. However, systemic immune remodeling and its effect on the bone marrow niche remain unclear.

Methods: Harnessing single-cell RNA sequencing, we compare the bone marrow immune cell landscape of wild-type (WT) mice and TH-MYCN transgenic mice.

Results: TH-MYCN mice showed increased neutrophils and Cd300e+ myeloid cells, and reduced developing B cells, mirroring our findings in human neuroblastoma bone marrow metastases. Ligand-receptor analysis revealed enrichment of ADGRG and SEMA4 signaling pathways in TH-MYCN bone marrow, highlighting Tgm2-Adgrg1, Sema4D-Plxnb2, and Sema4D-Cd72 interactions as potential immune modulators. In contrast, CD45 and CEACAM pathways were prominent in WT mice, suggesting context-specific immune regulation. A distinct Cd300e+ Pecam1+ myeloid population enriched in TH-MYCN mice, exhibited a gene signature, including Fabp4, Ear2 (Nr2f6), and Treml4, genes associated with neuroblastoma staging and poor survival. FABP4+ macrophages, enriched in MYCN-amplified neuroblastoma relapse, have been implicated in enhancing tumor cell migration, invasion, and growth.

Conclusions: Our data reveals the distant influence of primary tumors on bone marrow immune composition and signaling. These insights into bone marrow immune remodeling highlight FABP4+ macrophages and semaphorin signaling as potential immunotherapeutic targets to disrupt neuroblastoma progression.