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

Abstract

Abstract 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 (FLs) and bone marrow using single-cell RNA sequencing, immunofluorescence imaging, and functional assays. We describe 3 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 FLs, demonstrating potent immunosuppressive effects on T cells. This subset’s gene signature was correlated with shorter overall survival (OS) in a large data set of patients with MM, 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.