Davies F E, Raje N, Hideshima T, Lentzsch S, Young G, Tai Y T, Lin B, Podar K, Gupta D, Chauhan D, Treon S P, Richardson P G, Schlossman R L, Morgan G J, Muller G W, Stirling D I, Anderson K C
Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Blood. 2001 Jul 1;98(1):210-6. doi: 10.1182/blood.v98.1.210.
The antiangiogenic activity of thalidomide (Thal), coupled with an increase in bone marrow angiogenesis in multiple myeloma (MM), provided the rationale for the use of Thal in MM. Previously, the direct anti-MM activity of Thal and its analogues (immunomodulatory drugs, IMiDs) on MM cells was demonstrated, suggesting multiple mechanisms of action. In this study, the potential immunomodulatory effects of Thal/IMiDs in MM were examined. It was demonstrated that Thal/IMiDs do not induce T-cell proliferation alone but act as costimulators to trigger proliferation of anti-CD3-stimulated T cells from patients with MM, accompanied by an increase in interferon-gamma and IL-2 secretion. However, an increase in autologous T-cell killing of patient MM cells could not be demonstrated. A role for natural killer (NK)- and LAK-cell-mediated killing is suggested because IL-2-primed peripheral blood mononuclear cells (PBMCs) treated with Thal/IMiDs demonstrated significantly increased lysis of MM cell lines. Cold target inhibition assays suggested NK- rather than LAK-cell-mediated killing. Furthermore, this killing was not major histocompatibility complex-class restricted, and the depletion of CD56(+) cells blocked the drug-induced MM cell lysis. It was significant that increased killing of patient MM cells by autologous PBMCs treated with Thal/IMiDs was also observed. Although the in vivo relevance of NK-cell-mediated MM cell killing is unknown, phenotypic analysis performed in MM patients receiving Thal therapy demonstrated an increase in CD3(-)CD56(+) cells in patients responding to therapy. Thus in vitro and in vivo data support the hypothesis that Thal may mediate its anti-MM effect, at least in part, by modulating NK cell number and function.
沙利度胺（Thal）的抗血管生成活性，加之多发性骨髓瘤（MM）中骨髓血管生成增加，为Thal用于MM提供了理论依据。此前，已证实Thal及其类似物（免疫调节药物，IMiDs）对MM细胞具有直接抗MM活性，提示其作用机制多样。在本研究中，检测了Thal/IMiDs在MM中的潜在免疫调节作用。结果表明，Thal/IMiDs单独并不诱导T细胞增殖，但作为共刺激剂触发MM患者抗CD3刺激的T细胞增殖，同时伴有干扰素-γ和IL-2分泌增加。然而，未证实患者MM细胞的自体T细胞杀伤作用增强。提示自然杀伤（NK）细胞和淋巴因子激活的杀伤细胞（LAK）介导的杀伤作用发挥了作用，因为用Thal/IMiDs处理的IL-2预刺激外周血单个核细胞（PBMCs）对MM细胞系的裂解作用显著增强。冷靶抑制试验提示是NK细胞而非LAK细胞介导的杀伤作用。此外，这种杀伤作用不受主要组织相容性复合体I类限制，CD56(+)细胞的耗竭可阻断药物诱导的MM细胞裂解。同样值得注意的是，也观察到用Thal/IMiDs处理的自体PBMCs对患者MM细胞的杀伤作用增强。尽管NK细胞介导的MM细胞杀伤作用在体内的相关性尚不清楚，但对接受Thal治疗的MM患者进行的表型分析显示，治疗有反应的患者中CD3(-)CD56(+)细胞增加。因此，体外和体内数据支持以下假说：Thal至少部分地通过调节NK细胞数量和功能来介导其抗MM作用。
