Immunoregulatory roles of versican proteolysis in the myeloma microenvironment
Immunoregulatory roles of versican proteolysis in the myeloma microenvironment
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DOI：
10.1182/blood-2016-03-705780
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发表时间：
2016-08-04
期刊：
影响因子：
20.3
通讯作者：
Asimakopoulos, Fotis
中科院分区：
文献类型：
--
作者：
Hope, Chelsea;Foulcer, Simon;Asimakopoulos, Fotis
骨髓瘤的免疫监测仍然不完全清楚。我们已经证明了骨髓瘤肿瘤中基质蛋白聚糖多功能蛋白聚糖（VCAN）的蛋白水解加工。尽管完整的VCAN通过Toll样受体2（TLR 2）结合发挥致耐受性活性，但VCAN蛋白水解的免疫调节后果仍然未知。在这里，我们表明，显示CD 8（+）浸润/聚集的人骨髓瘤肿瘤在预测产生糖胺聚糖缺失的N-末端片段versikine的位点经历了VCAN蛋白水解。骨髓瘤相关巨噬细胞（MAMs），而不是肿瘤细胞，主要产生V1-VCAN，前体versikine，而基质细胞衍生的ADAMTS 1是最强劲的表达VCAN降解蛋白酶。纯化的versikine诱导人骨髓瘤骨髓源MAMs早期表达炎性细胞因子白细胞介素1 β（IL-1 β）和IL-6。我们发现versikine通过依赖和独立于Tpl 2激酶的途径进行信号传导，Tpl 2激酶是巨噬细胞中核因子κ B1介导的MAPK活化的关键调节因子。与完整的VCAN不同，versikine诱导的IL-6产生部分独立于Tlr 2。在巨噬细胞-骨髓瘤细胞串扰模型中，versikine诱导“T细胞炎症”的组分，包括IRF 8依赖性I型干扰素转录特征和T细胞化学引诱物CCL 2。因此，骨髓瘤微环境中基质细胞和骨髓细胞之间的相互作用产生versikine，一种新的生物活性损伤相关分子模式，可促进骨髓瘤肿瘤的免疫感应并调节完整VCAN积累的致耐受性后果。治疗性versikine给药可增强T细胞活化免疫疗法。
Myeloma immunosurveillance remains incompletely understood. We have demonstrated proteolytic processing of the matrix proteoglycan, versican (VCAN), in myeloma tumors. Whereas intact VCAN exerts tolerogenic activities through Toll-like receptor 2 (TLR2) binding, the immunoregulatory consequences of VCAN proteolysis remain unknown. Here we show that human myeloma tumors displaying CD8(+) infiltration/aggregates underwent VCAN proteolysis at a site predicted to generate a glycosaminoglycan-bereft N-terminal fragment, versikine. Myeloma-associated macrophages (MAMs), rather than tumor cells, chiefly produced V1-VCAN, the precursor to versikine, whereas stromal cell-derived ADAMTS1 was the most robustly expressed VCAN-degrading protease. Purified versikine induced early expression of inflammatory cytokines interleukin 1 beta (IL-1 beta) and IL-6 by human myeloma marrow-derived MAMs. We show that versikine signals through pathways both dependent and independent of Tpl2 kinase, a key regulator of nuclear factor kappa B1-mediated MAPK activation in macrophages. Unlike intact VCAN, versikine-induced Il-6 production was partially independent of Tlr2. In a model of macrophage-myeloma cell crosstalk, versikine induced components of "T-cell inflammation," including IRF8-dependent type I interferon transcriptional signatures and T-cell chemoattractant CCL2. Thus the interplay between stromal cells and myeloid cells in the myeloma microenvironment generates versikine, a novel bioactive damage-associated molecular pattern that may facilitate immune sensing of myeloma tumors and modulate the tolerogenic consequences of intact VCAN accumulation. Therapeutic versikine administration may potentiate T-cell-activating immunotherapies.