Deciphering neutrophil dynamics in the focal lesion tumor microenvironment to overcome immunosuppression in multiple myeloma Open Access

• Three distinct neutrophil subsets identified, with immunosuppressive CD10+ TREM1+ CXCR2+ neutrophils dominating the TME.

• CXCR2 blockade suppresses neutrophil activity and enhances anti-tumor immune responses to standard treatments in multiple myeloma models.

Understanding the roles of myeloid cells in the tumor microenvironment (TME) has emerged as a promising strategy to identify novel targets to counteract the immunosuppressive barriers protecting multiple myeloma (MM). Neutrophils are a new cancer research focus due to their potential to reduce the efficacy of immune-based therapies. This study aimed to deepen understanding of neutrophil function in MM by analyzing freshly isolated myeloid cells from paired focal lesions (FL) and bone marrow (BM) using single-cell RNA sequencing (scRNA-seq), immunofluorescence imaging, and functional assays. We describe three distinct CXCR2+ mature neutrophil subsets: TREM1+CD10+, RETN+LCN2+, and TNFAIP3+CXCL8+, each exhibiting unique phenotypes within the TME. Notably, the TREM1+CD10+ subset was highly prevalent, particularly in FL, demonstrating potent immunosuppressive effects on T cells. This subset's gene signature was correlated with shorter overall survival (OS) in a large MM patient dataset, underscoring its clinical significance. Targeted inhibition of neutrophil activity through CXCR2 blockade, alone or combined with standard anti-MM therapies, significantly reduced tumor burden, improving OS in preclinical MM models. These insights into neutrophil-mediated immunosuppression in MM provide valuable knowledge regarding mechanisms driving immune evasion and reveal new therapeutic approaches to enhance the efficacy of MM treatment.