Paper

An IL-1β driven neutrophil-stromal cell axis fosters a BAFF-rich microenvironment in multiple myeloma

Gregory Van Beek, Teddie Van Heusden, Moreau, Philippe, Bruns, Heiko, Vermeulen, Michael, Broijl, Annemiek, Büttner-Herold, Maike, Hoogenboezem, Remco, Cupedo, Tom, Mark Van Duin, Sanders, Mathijs A, Gay, Francesca, Fokkema, Cathelijne, De Jong, Madelon Me, Sonneveld, Pieter, Van De Woestijne, Pieter, Papazian, Natalie, Sabrin Tahri

2023

Overview

The bone marrow is 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 feedforward 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.Footnotes* https://www.bmbrowser.org* https://github.com/MyelomaRotterdam

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: BLyS protein / Bone marrow / Bone tumors / Cell activation / Cell survival / IL-1β / Immunology / Inflammation / Leukocytes (neutrophilic) / Malignancy / Microenvironments / Multiple myeloma / Neutrophils / Stat3 protein / Stromal cells / Survival factor