Asimakopoulos Fotis, Hope Chelsea, Johnson Michael G, Pagenkopf Adam, Gromek Kimberly, Nagel Bradley
Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA;
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
J Leukoc Biol. 2017 Aug;102(2):265-275. doi: 10.1189/jlb.3MR1116-468R. Epub 2017 Mar 2.
The last 10-15 years have witnessed a revolution in treating multiple myeloma, an incurable cancer of Ab-producing plasma cells. Advances in myeloma therapy were ushered in by novel agents that remodel the myeloma immune microenvironment. The first generation of novel agents included immunomodulatory drugs (thalidomide analogs) and proteasome inhibitors that target crucial pathways that regulate immunity and inflammation, such as NF-κB. This paradigm continued with the recent regulatory approval of mAbs (elotuzumab, daratumumab) that impact both tumor cells and associated immune cells. Moreover, recent clinical data support checkpoint inhibition immunotherapy in myeloma. With the success of these agents has come the growing realization that the myeloid infiltrate in myeloma lesions-what we collectively call the myeloid-in-myeloma compartment-variably sustains or deters tumor cells by shaping the inflammatory milieu of the myeloma niche and by promoting or antagonizing immune-modulating therapies. The myeloid-in-myeloma compartment includes myeloma-associated macrophages and granulocytes, dendritic cells, and myeloid-derived-suppressor cells. These cell types reflect variable states of differentiation and activation of tumor-infiltrating cells derived from resident myeloid progenitors in the bone marrow-the canonical myeloma niche-or myeloid cells that seed both canonical and extramedullary, noncanonical niches. Myeloma-infiltrating myeloid cells engage in crosstalk with extracellular matrix components, stromal cells, and tumor cells. This complex regulation determines the composition, activation state, and maturation of the myeloid-in-myeloma compartment as well as the balance between immunogenic and tolerogenic inflammation in the niche. Redressing this balance may be a crucial determinant for the success of antimyeloma immunotherapies.
在过去的10到15年里，多发性骨髓瘤（一种无法治愈的产生抗体的浆细胞癌症）的治疗发生了一场革命。骨髓瘤治疗的进展是由重塑骨髓瘤免疫微环境的新型药物引领的。第一代新型药物包括免疫调节药物（沙利度胺类似物）和蛋白酶体抑制剂，它们靶向调节免疫和炎症的关键途径，如核因子κB。随着单克隆抗体（埃罗妥珠单抗、达雷妥尤单抗）最近获得监管批准，这一模式得以延续，这些单克隆抗体对肿瘤细胞和相关免疫细胞均有影响。此外，最近的临床数据支持在骨髓瘤中进行检查点抑制免疫疗法。随着这些药物的成功，人们越来越意识到，骨髓瘤病变中的髓系浸润——我们统称为骨髓瘤中的髓系区室——通过塑造骨髓瘤生态位的炎症环境以及促进或拮抗免疫调节疗法，以不同方式维持或抑制肿瘤细胞。骨髓瘤中的髓系区室包括骨髓瘤相关巨噬细胞和粒细胞、树突状细胞以及髓系来源的抑制细胞。这些细胞类型反映了源自骨髓中常驻髓系祖细胞（典型的骨髓瘤生态位）或播种于典型和髓外非典型生态位的髓系细胞的肿瘤浸润细胞的不同分化和激活状态。浸润骨髓瘤的髓系细胞与细胞外基质成分、基质细胞和肿瘤细胞相互作用。这种复杂的调节决定了骨髓瘤中的髓系区室的组成、激活状态和成熟度，以及生态位中免疫原性炎症和耐受性炎症之间的平衡。纠正这种平衡可能是抗骨髓瘤免疫疗法成功的关键决定因素。
