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

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.