High-Resolution Single-Cell RNA Sequencing Uncovers Disparate Neutrophil Populations within Metastatic Cancer Lesions Linked to Progression Free Survival in Multiple Myeloma Patients

ABSTRACT: Understanding the myeloid cell biology of the tumor microenvironment (TME) will allow discovery of novel strategies to disrupt the local immunosuppressive milieu and to develop effective immune based therapies. Neutrophils are a major, understudied myeloid cell population in metastatic malignant tumors. Here, we studied myeloid cells freshly sorted from paired focal lesions (FL) (osteolytic lesions and plasmacytomas) and pelvic bone marrow (BM) from multiple myeloma (MM) patients. Using single cell RNA sequencing and functional assays, we discovered the emergence and expansion of distinct, late-stage neutrophil subsets with potent immunosuppressive signatures predominantly in FL. The most abundant late-stage neutrophil subset, MM_N_FL1, activates cytokine responses, the IL-8 CXCR2 pathway, and nitrogen compound metabolism while downregulating primary, secondary, and tertiary granule expression. FL neutrophils exhibit transcriptional and functional differences compared to their paired BM counterparts, displaying notably elevated immunosuppressive capacities independent of tumor cell percentage in FL and BM. Furthermore, the gene signature of the FL neutrophils was associated with significantly inferior progression-free survival (PFS) in a defined population of MM patients. The study provides an in-depth analysis of neutrophil dynamics, function, and imbalance in MM patient FL, suggesting promising targets for novel clinical immunomodulatory therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261171 | GEO | 2025/10/22

REPOSITORIES: GEO