Drug-Induced Senescent Multiple Myeloma Cells Elicit NK Cell Proliferation by Direct or Exosome-Mediated IL15 Trans-Presentation
Drug-Induced Senescent Multiple Myeloma Cells Elicit NK Cell Proliferation by Direct or Exosome-Mediated IL15 Trans-Presentation
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DOI：
10.1158/2326-6066.cir-17-0604
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发表时间：
2018-07-01
影响因子：
10.1
通讯作者：
Soriani, Alessandra
中科院分区：
文献类型：
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作者：
Borrelli, Cristiana;Ricci, Biancamaria;Soriani, Alessandra
用亚致死剂量的遗传毒性药物治疗多发性骨髓瘤（MM）细胞导致衰老，并导致NK细胞识别和效应功能增加。在此，我们展示了。多柔比星和美法仑处理的衰老细胞显示出IL 15表达增加，IL 15是一种参与NK细胞活化、增殖和成熟的细胞因子。在MM细胞系和来自患者骨髓（BM）抽吸物的恶性浆细胞中，IL 15上调在mRNA和蛋白质水平上是明显的。然而，IL 15仅在体内作为可溶性细胞因子可检测到，因此表明IL 15在BM肿瘤微环境中的功能作用。IL 15的增加伴随着IL 15/IL 15 RA复合物在衰老骨髓瘤细胞膜上的表达增强，允许该细胞因子功能性反式呈递给邻近的NK细胞，其因此经历活化和增殖。我们证明，MM细胞衍生的外泌体，其释放通过美法仑处理在衰老细胞中增强，也表达IL 15 RA和IL 15，并且它们在外源性IL 15存在下与NK细胞的相互作用导致增殖增加。总之，我们的数据表明，低剂量的化疗药物，通过诱导肿瘤细胞衰老和衰老相关的分泌表型，促进IL 15反式呈递给NK细胞，反过来，它们的激活和增殖，从而增强NK细胞-肿瘤免疫监视，并提供新的见解，为开发衰老冲洗癌症治疗。(C)2018年AACR。
Treatment of multiple myeloma (MM) cells with sublethal doses of genotoxic drugs leads w senescence and results in increased NK cell recognition and effector functions. Herein, we demonstrated. that doxorubicin- and melphalan-treated senescent cells display increased expression of 1L15, a cytokine involved in NK cell activation, proliferation, and maturation. IL15 upregulation was evident at the mRNA and protein level, both in MM cell lines and malignant plasma cells from patients' bone marrow (BM) aspirates. However, IL15 was detectable as a soluble cytokine only in vivo, thus indicating a functional role of IL15 in the BM tumor microenvironment. The increased IL15 was accompanied by enhanced expression of the IL15/IL15RA complex on the membrane of senescent myeloma cells, allowing the functional trans-presentation of this cytokine to neighboring NK cells, which consequently underwent activation and proliferation. We demonstrated that MM cell-derived exosomes, the release of which was augmented by melphalan treatment in senescent cells, also expressed IL15RA and 1L15, and their interaction with NK cells in the presence of exogenous IL15 resulted in increased proliferation. Altogether, our data demonstrated that low doses of chemotherapeutic drugs, by inducing tumor cell senescence and a senescence-associated secretory phenotype, promoted IL15 trans-presentation to NK cells and, in turn, their activation and proliferation, thus enhancing NK cell-tumor immune surveillance and providing new insights for the exploitation of senescence-hosed cancer therapies. (C) 2018 AACR.