IL-12 enhances the natural killer cell cytokine response to Ab-coated tumor cells
IL-12 enhances the natural killer cell cytokine response to Ab-coated tumor cells
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DOI：
10.1172/jci200215950
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发表时间：
2002-10-01
影响因子：
15.9
通讯作者：
Carson, WE
中科院分区：
文献类型：
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作者：
Parihar, R;Dierksheide, J;Carson, WE
针对肿瘤细胞生长受体的重组mAb的抗肿瘤活性通常被认为是由直接的抗增殖作用、诱导细胞凋亡或可能的针对肿瘤靶点介导的Ab依赖性细胞毒性引起的。然而，目前尚不清楚这些机制在何种程度上实际上有助于体内Ab包被的肿瘤细胞的清除。我们在这里表明，NK细胞分泌一个独特的配置文件的有效的免疫刺激细胞因子在双重刺激抗体包被的肿瘤细胞和IL-12。这种反应不能通过与其他IL的共刺激来复制，并且在单核细胞的存在下显著增强。细胞因子的产生依赖于IgG Fc部分的活化受体（Fc γ RIII）和NK细胞上表达的IL-12受体介导的协同信号。将Ab包被的肿瘤细胞和IL-12共同给予BALB/c小鼠导致NK细胞衍生的细胞因子的循环水平增强，具有增强抗肿瘤免疫的能力。这些发现表明，除了介导细胞毒性和细胞凋亡之外，mAb的抗肿瘤活性也可能是由于能够识别mAb包被的靶标的免疫效应物内的有效细胞因子分泌程序的激活。
The anti-tumor activity of recombinant mAb's directed against tumor cell growth receptors has generally been considered to result from direct antiproliferative effects, the induction of apoptosis, or possibly Ab-dependent cellular cytotoxicity mediated against tumor targets. However, it remains unclear to what degree these mechanisms actually aid in the clearance of Ab-coated tumor cells in vivo. We show here that NK cells secrete a distinct profile of potent immunostimulatory cytokines in response to dual stimulation with Ab-coated tumor cells and IL-12. This response could not be duplicated by costimulation with other ILs and was significantly enhanced in the presence of monocytes. Cytokine production was dependent upon synergistic signals mediated by the activating receptor for the Fc portion of IgG (FcgammaRIII) and the IL-12 receptor expressed on NK cells. Coadministration of Ab-coated tumor cells and IL-12 to BALB/c mice resulted in enhanced circulating levels of NK cell-derived cytokines with the capacity to augment anti-tumor immunity. These findings suggest that, in addition to mediating cellular cytotoxicity and apoptosis, the anti-tumor activity of mAb's might also result from activation of a potent cytokine secretion program within immune effectors capable of recognizing mAb-coated targets.