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

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 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 Statement M.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.