de Jong Madelon M E, Fokkema Cathelijne, Papazian Natalie, Czeti Ágnes, Appelman Marjolein K, Vermeulen Michael, van Heusden Teddie, Hoogenboezem Remco M, van Beek Gregory, Tahri Sabrin, Sanders Mathijs A, van de Woestijne Pieter C, Gay Francesca, Moreau Philippe, Büttner-Herold Maike, Bruns Heiko, van Duin Mark, Broijl Annemiek, Sonneveld Pieter, Cupedo Tom
Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands.
Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Nat Immunol. 2024 May;25(5):820-833. doi: 10.1038/s41590-024-01808-x. Epub 2024 Apr 10.
Human bone marrow permanently harbors high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In individuals with multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. We investigated myeloma-associated alterations in human marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor supportive and transcribe increased levels of IL1B and myeloma cell survival factor TNFSF13B (BAFF). Interactions with inflammatory stromal cells 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 antimyeloma treatment, human 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.
人类骨髓中永久存在大量中性粒细胞，这些细胞的肿瘤支持性偏向可能会对局限于骨髓的恶性肿瘤产生重大影响。在多发性骨髓瘤患者中，骨髓的特征是具有影响中性粒细胞潜力的炎性基质细胞。我们研究了人类骨髓中性粒细胞中与骨髓瘤相关的改变以及基质炎症对中性粒细胞功能的影响。骨髓瘤骨髓中的成熟中性粒细胞被激活并具有肿瘤支持性，且转录出更高水平的白细胞介素1β（IL1B）和骨髓瘤细胞存活因子肿瘤坏死因子配体超家族成员13B（TNFSF13B，也称为BAFF）。与炎性基质细胞的相互作用以信号转导和转录激活因子3（STAT3）依赖的方式诱导中性粒细胞激活，包括BAFF分泌，一旦被激活，中性粒细胞就获得了相互诱导基质激活的能力。在一线骨髓清除性抗骨髓瘤治疗后，人类骨髓仍保留残余的基质炎症，新形成的中性粒细胞会被重新激活。综合来看，我们发现了一个中性粒细胞-基质细胞前馈环，它驱动着肿瘤支持性炎症，这种炎症在治疗后仍然持续，因此需要新的策略来靶向多发性骨髓瘤中的基质和免疫微环境。
