PT  - JOURNAL ARTICLE
AU  - Madelon M.E. de Jong
AU  - Cathelijne Fokkema
AU  - Natalie Papazian
AU  - Teddie van Heusden
AU  - Michael Vermeulen
AU  - Remco Hoogenboezem
AU  - Gregory van Beek
AU  - Sabrin Tahri
AU  - Mathijs A. Sanders
AU  - Pieter van de Woestijne
AU  - Francesca Gay
AU  - Philippe Moreau
AU  - Maike Büttner-Herold
AU  - Heiko Bruns
AU  - Mark van Duin
AU  - Annemiek Broijl
AU  - Pieter Sonneveld
AU  - Tom Cupedo
TI  - An IL-1β driven neutrophil-stromal cell axis fosters a BAFF-rich microenvironment in multiple myeloma
AID  - 10.1101/2023.03.03.530773
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.03.03.530773
4099  - http://biorxiv.org/content/early/2023/03/06/2023.03.03.530773.short
4100  - http://biorxiv.org/content/early/2023/03/06/2023.03.03.530773.full
AB  - The bone marrow permanently harbors high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. We investigated myeloma-associated alterations in marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor-supportive, transcribing increased levels of IL-1β, and myeloma cell survival factor BAFF. Interactions with inflammatory stromal cells can induce neutrophil activation, including BAFF secretion, in a STAT3-dependent manner and once activated, neutrophils gain the ability to reciprocally induce stromal activation. After first-line myeloid-depleting treatment, patient bone marrow retains residual stromal inflammation and newly-formed neutrophils are reactivated. Combined, we identify a neutrophil-stromal cell feed-forward loop driving tumor-supportive inflammation that persists after treatment and warrants novel strategies to target both stromal and immune microenvironments in multiple myeloma.Competing Interest StatementM.B.H.: speaker's fees from Sanofi and Pfizer, workshop sponsoring Novartis. F.G.: advisory boards and honoraria from Amgen, Celgene, Janssen, Takeda, BMS, AbbVie, and GlaxoSmithKline, and advisory boards of Roche, Adaptive Biotechnologies, Oncopeptides, bluebird bio and Pfizer. P.M.: advisory boards and honoraria of Janssen. A.B.: advisory boards and honoraria from Janssen, Sanofi, Amgen, BMS. P.S.: advisory boards and research funding of Karyopharm, Janssen, Amgen, Celgene and BMS, advisory board of Pfizer.