Investigating the Role of Neutrophil Extracellular Traps (NETs) in Multiple Myeloma Pathogenesis and Disease Evolution

Neutrophils implement a variety of mechanisms to fight infection and neutralize pathogens, including phagocytosis and degranulation, as well as the more recently characterized release of neutrophil extracellular traps (NETs) termed NETosis. NETs are web-like DNA structures combined with histones and antimicrobial proteins that are released from stimulated neutrophils. Stimulated neutrophils migrate and accumulate at the site of infection and eliminate microbes by phagocytosis, reactive oxygen species (ROS) production, and cytoplasmic granule release. The landscape of NETs in cancer is quickly changing as current basic and clinical research is providing evidence substantiating the role of neutrophils in cancer progression and therapeutic resistance. Several studies support the functional role of NETs in cancer therapeutic resistance, involving T-cell exhaustion, drug detoxification, angiogenesis, epithelial-to-mesenchymal transition, and extracellular matrix remodeling mechanisms. Previously, our group performed a mass spectrometry-based label-free quantitative proteomics analysis of bone marrow mononuclear cells (BMNCs) and blood plasma from multiple myeloma (MM) patients with and without extramedullary spread (soft tissue plasmacytomas) (PMID: 37568580). Pathway analysis identified neutrophil extracellular trap formation associated proteins (including proto-oncogene tyrosine-protein kinase Src (SRC) and spleen tyrosine kinase (SYK)), as significantly increased in patients with extramedullary myeloma (EMM). To assess NET formation in EMM based on a secreted/shed protein signature, plasma concentrations of the main NETosis markers, neutrophil elastase (ELA2), myeloperoxidase (MPO), citrullinated histone H3 (CitH3), and circulating nucleosomes, were evaluated using enzyme-linked immunosorbent assays (ELISAs). Plasma levels of ELA2 were significantly increased in EMM patients compared to MM (no evidence of extramedullary spread), while MPO plasma levels showed a trend towards increased concentrations in EMM patients. Building upon the hypothesis that NETs could play a role in the establishment of resistance/aggressive disease, future clinical applications could involve both monitoring and pharmacological targeting of NETs to predict and improve response to therapy.

Heckman:Zentalis Pharmaceuticals: Research Funding; Autolus Ltd.: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Novartis: Research Funding; Oncopeptides: Research Funding; WNTResearch: Research Funding; Kronos Bio: Research Funding.