Plasma cell derived mtDAMPs activate macrophage STING pathway which promotes myeloma progression

Jibril, Aisha, Hellmich, Charlotte, Wojtowicz, Edyta E., Hampton, Katherine, Maynard, Rebecca, De Silva, Ravindu ORCID:, Fowler-Shorten, Dominic J., Mistry, Jayna J., Moore, Jamie A., Bowles, Kristian M. ORCID: and Rushworth, Stuart A. (2023) Plasma cell derived mtDAMPs activate macrophage STING pathway which promotes myeloma progression. Blood, 141 (25). 3065–3077. ISSN 0006-4971

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Mitochondrial damage-associated molecular patterns (mtDAMPs) include proteins, lipids, metabolites and DNA and have various context specific immunoregulatory functions. Cell-free mitochondrial DNA (mtDNA) is recognised via pattern recognition receptors and is a potent activator of the innate immune system. Cell-free mtDNA is elevated in the circulation of trauma and cancer patients, however the functional consequences of elevated mtDNA are largely undefined. Multiple myeloma (MM) relies upon cellular interactions within the bone marrow (BM) microenvironment for survival and progression. Here, using in-vivo models, we describe the role of MM cell derived mtDAMPs in the pro-tumoral BM microenvironment, and the mechanism and functional consequence of mtDAMPs in myeloma disease progression. Initially, we identified elevated levels of mtDNA in the peripheral blood serum of MM patients compared to healthy controls. Using the MM1S cells engrafted into NSG mice we established that elevated mtDNA was derived from MM cells. We further show that BM macrophages sense and respond to mtDAMPs through the STING pathway and inhibition of this pathway reduces MM tumor-burden in the KaLwRij-5TGM1 mouse model. Moreover, we found that MM derived mtDAMPs induced upregulation of chemokine signatures in BM macrophages and inhibition of this signature resulted in egress of MM cells from the BM. Here, we demonstrate that malignant plasma cells release mtDNA, a form of mtDAMPs, into the myeloma BM microenvironment, which in turn activates macrophages via STING signalling. We establish the functional role of these mtDAMP-activated macrophages in promoting disease progression and retaining MM cells in the pro-tumoral BM microenvironment.

Item Type: Article
Additional Information: Funding Information: This work was supported by a Sir Henry Welcome Postdoctoral Fellowship (213731/Z/18/Z) (E.E.W.), Rosetrees Trust (J.A.M.), a Wellcome Trust Clinical Research Fellowship (220534/Z/20/Z) (C.H.), the Medical Research Council project (MR/T02934X/1) (S.A.R.). The authors acknowledge support by a grant from the Biotechnology and Biological Sciences Research Council, part of UK Research and Innovation’s Core Capability (grant BB/CCG1720/1); the National Capability (BBS/E/T/000PR9816); and the Norfolk and Norwich University Hospital Charitable Fund.
Uncontrolled Keywords: hematology,biochemistry,cell biology,immunology,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/2700/2720
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies
Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
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Depositing User: LivePure Connector
Date Deposited: 14 Mar 2023 11:30
Last Modified: 19 May 2024 06:32
DOI: 10.1182/blood.2022018711


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