Roda Julie M, Parihar Robin, Magro Cynthia, Nuovo Gerard J, Tridandapani Susheela, Carson William E
Integrated Biomedical Sciences Graduate Program, The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA.
Cancer Res. 2006 Jan 1;66(1):517-26. doi: 10.1158/0008-5472.CAN-05-2429.
In the current report, we have examined the ability of natural killer (NK) cells to produce T cell-recruiting chemokines following dual stimulation with interleukin (IL)-2 or IL-12 and human breast cancer cells coated with an antitumor antibody (trastuzumab). NK cells stimulated in this manner secreted an array of T cell-recruiting chemotactic factors, including IL-8, macrophage-derived chemokine, macrophage inflammatory protein 1alpha (MIP-1alpha), monocyte chemoattractant protein 1, and regulated on activation, normal T-cell expressed and secreted (RANTES), whereas stimulation of NK cells with either agent alone had minimal effect. Furthermore, these factors were functional for T-cell chemotaxis as culture supernatants derived from costimulated NK cells induced migration of both naïve and activated T cells in an in vitro chemotaxis assay. T-cell migration was significantly reduced when neutralizing antibodies to IL-8, MIP-1alpha, or RANTES were added to culture supernatants before their use in the chemotaxis assay. In addition, coadministration of trastuzumab-coated tumor cells and IL-12 to mice led to enhanced serum MIP-1alpha. As a clinical correlate, we examined the chemokine content of serum samples from breast cancer patients enrolled on a phase I trial of trastuzumab and IL-12, and found elevated levels of IL-8, RANTES, IFN-gamma inducible protein 10, monokine induced by IFN-gamma, and MIP-1alpha, specifically in those patients that experienced a clinical benefit. Sera from these patients exhibited the ability to direct T-cell migration in a chemotaxis assay, and neutralization of chemokines abrogated this effect. These data are the first to show chemokine production by NK cells, specifically in response to stimulation with antibody-coated tumor cells, and suggest a potential role for NK cell-derived chemokines in patients receiving therapeutic monoclonal antibodies.
在本报告中，我们研究了自然杀伤（NK）细胞在白细胞介素（IL）-2或IL-12与包被有抗肿瘤抗体（曲妥珠单抗）的人乳腺癌细胞双重刺激后产生T细胞招募趋化因子的能力。以这种方式刺激的NK细胞分泌了一系列T细胞招募趋化因子，包括IL-8、巨噬细胞衍生趋化因子、巨噬细胞炎性蛋白1α（MIP-1α）、单核细胞趋化蛋白1以及活化正常T细胞表达和分泌调控因子（RANTES），而单独用任何一种试剂刺激NK细胞的效果都微乎其微。此外，这些因子对T细胞趋化具有功能性，因为来自共刺激NK细胞的培养上清液在体外趋化试验中可诱导幼稚T细胞和活化T细胞迁移。在趋化试验中使用之前，向培养上清液中加入针对IL-8、MIP-1α或RANTES的中和抗体时，T细胞迁移显著减少。此外，将包被曲妥珠单抗的肿瘤细胞与IL-12共同给予小鼠会导致血清MIP-1α升高。作为临床关联，我们检测了参加曲妥珠单抗和IL-12 I期试验的乳腺癌患者血清样本中的趋化因子含量，发现IL-8、RANTES、γ干扰素诱导蛋白10、γ干扰素诱导单核因子和MIP-1α水平升高，特别是在那些有临床获益的患者中。这些患者的血清在趋化试验中表现出引导T细胞迁移的能力，趋化因子的中和消除了这种作用。这些数据首次表明NK细胞产生趋化因子，特别是对包被抗体的肿瘤细胞刺激的反应，并提示NK细胞衍生的趋化因子在接受治疗性单克隆抗体的患者中可能发挥作用。
