Tissue-resident macrophages promote early dissemination of multiple myeloma via IL-6 and TNFα
Tissue-resident macrophages promote early dissemination of multiple myeloma via IL-6 and TNFα
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DOI：
10.1182/bloodadvances.2021005327
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发表时间：
2021-09-22
期刊：
影响因子：
7.5
通讯作者：
Fooksman, David
中科院分区：
文献类型：
--
作者：
Akhmetzyanova, Ilseyar;Aaron, Tonya;Fooksman, David
多发性骨髓瘤（MM）是一种浆细胞恶性肿瘤，其特征是在骨骼中存在多个病灶。这些不同的肿瘤病灶代表了肿瘤生长和扩散的周期，这些周期会产生新的簇并推动疾病进展。通过使用胫骨内Vk*MYC小鼠骨髓瘤模型，我们发现CD 169（+）耐辐射的组织驻留巨噬细胞（MP）对骨髓瘤的早期传播和疾病进展至关重要。这些MP的消耗对肿瘤增殖没有影响，但它确实减少了骨髓瘤从骨髓（BM）中的排出及其向其他骨骼的扩散。MP耗竭作为单一疗法以及与BM移植联合使用可改善总体生存率。骨髓瘤的扩散与BM MP中增加的炎症特征相关。它还与肿瘤相关MP产生的白细胞介素-6（IL-6）和肿瘤坏死因子α（TNF α）相关。外源性静脉内IL-6和TNF α可通过增加BM中的血管通透性和通过降低CD 138的粘附增强骨髓瘤细胞的运动性来触发BM中的骨髓瘤内渗。此外，缺乏IL-6的小鼠在播散骨髓瘤方面存在缺陷，与MP耗尽的受体类似。缺乏TNF α或TNF α受体（TNFR）的小鼠在播散MM方面存在缺陷，植入也受损。这些对骨髓瘤扩散的影响需要在含有这些抗辐射BM MP的抗辐射隔室中产生细胞因子。综上所述，我们认为骨髓瘤细胞从骨髓中的排出是由病灶中的局部炎症调节的，部分是由CD 169（+）MP驱动的。
Multiple myeloma (MM) is a plasma cell malignancy characterized by the presence of multiple foci in the skeleton. These distinct tumor foci represent cycles of tumor growth and dissemination that seed new clusters and drive disease progression. By using an intratibial Vk*MYC murine myeloma model, we found that CD169(+) radiation-resistant tissue-resident macrophages (MPs) were critical for early dissemination of myeloma and disease progression. Depletion of these MPs had no effect on tumor proliferation, but it did reduce egress of myeloma from bone marrow (BM) and its spread to other bones. Depletion of MPs as a single therapy and in combination with BM transplantation improved overall survival. Dissemination of myeloma was correlated with an increased inflammatory signature in BM MPs. It was also correlated with the production of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) by tumor-associated MPs. Exogenous intravenous IL-6 and TNF alpha can trigger myeloma intravasation in the BM by increasing vascular permeability in the BM and by enhancing the motility of myeloma cells by reducing the adhesion of CD138. Moreover, mice that lacked IL-6 had defects in disseminating myeloma similar to those in MP-depleted recipients. Mice that were deficient in TNF alpha or TNF alpha receptor (TNFR) had defects in disseminating MM, and engraftment was also impaired. These effects on dissemination of myeloma required production of cytokines in the radiation-resistant compartment that contained these radiation-resistant BM MPs. Taken together, we propose that egress of myeloma cells from BM is regulated by localized inflammation in foci, driven in part by CD169(+) MPs.