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

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 e...

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Vydáno v:Blood Ročník 146; číslo 20; s. 2392
Hlavní autoři: Rivera, Joshua, Yan, Qi, Daneshmandi, Saeed, Lannes, Romain, Katsuta, Eriko, Choi, JeeEun, Singh, Prashant, Belal, Ahmed, Alberico, Ronald, Lund, Ian, Schaefer, Megan, Hassan, Hamza, Parker, Sarah, Anderson, Kenneth C, Munshi, Nikhil C, Samur, Mehmet, McCarthy, Philip L, Hillengass, Jens, Mohammadpour, Hemn
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 13.11.2025
Témata:
Animals
Female
Humans
Immune Tolerance
Male
Mice
Multiple Myeloma - genetics
Multiple Myeloma - immunology
Multiple Myeloma - pathology
Neutrophils - immunology
Neutrophils - pathology
Receptors, Interleukin-8B
Tumor Microenvironment - immunology
ISSN:1528-0020, 1528-0020
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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.
AbstractList 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.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.
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.
Author Yan, Qi
Munshi, Nikhil C
Hassan, Hamza
McCarthy, Philip L
Singh, Prashant
Samur, Mehmet
Lannes, Romain
Alberico, Ronald
Lund, Ian
Mohammadpour, Hemn
Katsuta, Eriko
Rivera, Joshua
Choi, JeeEun
Daneshmandi, Saeed
Hillengass, Jens
Anderson, Kenneth C
Schaefer, Megan
Parker, Sarah
Belal, Ahmed
Author_xml – sequence: 1
  givenname: Joshua
  surname: Rivera
  fullname: Rivera, Joshua
  organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
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  givenname: Qi
  orcidid: 0000-0002-5963-9242
  surname: Yan
  fullname: Yan, Qi
  organization: Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
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  givenname: Saeed
  orcidid: 0000-0001-7817-3006
  surname: Daneshmandi
  fullname: Daneshmandi, Saeed
  organization: Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
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  givenname: Romain
  orcidid: 0000-0002-6672-1762
  surname: Lannes
  fullname: Lannes, Romain
  organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
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  givenname: Eriko
  orcidid: 0000-0001-5862-2919
  surname: Katsuta
  fullname: Katsuta, Eriko
  organization: Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Institute of Science Tokyo, Tokyo, Japan
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  surname: Choi
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  organization: Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
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  givenname: Prashant
  surname: Singh
  fullname: Singh, Prashant
  organization: Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY
– sequence: 8
  givenname: Ahmed
  surname: Belal
  fullname: Belal, Ahmed
  organization: Department of Diagnostic Radiology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
– sequence: 9
  givenname: Ronald
  surname: Alberico
  fullname: Alberico, Ronald
  organization: Department of Diagnostic Radiology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
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  givenname: Ian
  surname: Lund
  fullname: Lund, Ian
  organization: Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
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  givenname: Megan
  surname: Schaefer
  fullname: Schaefer, Megan
  organization: Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
– sequence: 12
  givenname: Hamza
  orcidid: 0000-0003-1775-2703
  surname: Hassan
  fullname: Hassan, Hamza
  organization: Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
– sequence: 13
  givenname: Sarah
  surname: Parker
  fullname: Parker, Sarah
  organization: Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
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  givenname: Kenneth C
  surname: Anderson
  fullname: Anderson, Kenneth C
  organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
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  givenname: Nikhil C
  surname: Munshi
  fullname: Munshi, Nikhil C
  organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
– sequence: 16
  givenname: Mehmet
  surname: Samur
  fullname: Samur, Mehmet
  organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
– sequence: 17
  givenname: Philip L
  orcidid: 0000-0002-9577-3879
  surname: McCarthy
  fullname: McCarthy, Philip L
  organization: Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
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  givenname: Jens
  orcidid: 0000-0002-1778-0010
  surname: Hillengass
  fullname: Hillengass, Jens
  organization: Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
– sequence: 19
  givenname: Hemn
  orcidid: 0000-0002-0158-7283
  surname: Mohammadpour
  fullname: Mohammadpour, Hemn
  organization: Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
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Copyright 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
Copyright © 2025 American Society of Hematology.
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SubjectTerms Animals
Female
Humans
Immune Tolerance
Male
Mice
Multiple Myeloma - genetics
Multiple Myeloma - immunology
Multiple Myeloma - pathology
Neutrophils - immunology
Neutrophils - pathology
Receptors, Interleukin-8B
Tumor Microenvironment - immunology
Title Deciphering neutrophil dynamics in the focal lesion tumor microenvironment to overcome immunosuppression in multiple myeloma
URI https://www.ncbi.nlm.nih.gov/pubmed/40758944
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