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

de Jong, M. M.; Fokkema, C.; Papazian, N.; van Heusden, T.; Vermeulen, M.; Hoogenboezem, R.; van Beek, G.; Tahri, S.; Sanders, M. A.; van de Woestijne, P.; Gay, F.; Moreau, P.; Büttner-Herold, M.; Bruns, H.; van Duin, M.; Broijl, A.; Sonneveld, P.; Cupedo, T.

doi:10.1101/2023.03.03.530773

bioRxiv · 10.1101/2023.03.03.530773

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

de Jong, M. M.·Fokkema, C.·Papazian, N.·van Heusden, T.·Vermeulen, M.·Hoogenboezem, R.·van Beek, G.·Tahri, S.·Sanders, M. A.·van de Woestijne, P.·Gay, F.·Moreau, P.·Büttner-Herold, M.·Bruns, H.·van Duin, M.·Broijl, A.·Sonneveld, P.·Cupedo, T.

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Abstract

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-1{beta}, 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.

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de Jong, M. M., Fokkema, C., Papazian, N., van Heusden, T., Vermeulen, M., Hoogenboezem, R., van Beek, G., Tahri, S., Sanders, M. A., van de Woestijne, P., Gay, F., Moreau, P., Büttner-Herold, M., Bruns, H., van Duin, M., Broijl, A., Sonneveld, P., Cupedo, T.. 2023-03-05. An IL-1β driven neutrophil-stromal cell axis fosters a BAFF-rich microenvironment in multiple myeloma. https://doi.org/10.1101/2023.03.03.530773

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