NK CELL RECEPTOR RECOGNITION OF ORAL CANCERS

描述（改编自研究者摘要）：背景：口腔 鳞状细胞癌（OC-SCC）可能对NK细胞监视敏感， 但对NK细胞受体和肿瘤细胞配体知之甚少， 涉案对NK受体表面密度知之甚少或一无所知，或 它们在触发不同效应子功能方面的相对效力。相比之下 对于KIR，HLA I类分子上的LIR-1和LIR-2识别表位是 不知道。一组独特的转化NK细胞模拟正常血液NK细胞。 单个NK细胞对造血细胞与OC-SCC细胞的反应不同， 以及原发性与转移性自体OC-SCC细胞。OC-SCC细胞刺激 NK IFN-γ通过细胞表面配体和IL-18的组合分泌，但 而不是IL-12。与T细胞不同，IL-18激活NK细胞不需要IL-12。NK 细胞被固定的或Fc受体结合的抗受体mAb激活， 剂量依赖性和时间依赖性方式。LIR-I/IG融合蛋白结合 选择性HLA转染子，表明通过E63-K66盐桥的抑制。 本提案的实验计划将1A）寻找不同的NK细胞 对OC-SCC细胞的反应模式，并鉴定NK受体和OC-SCC配体 其激活细胞毒性和IFN-γ分泌，1B）表征OC-SCC如何 IL-18和细胞表面配体共刺激原发性巨噬细胞NK IFN-γ分泌 和转移性OC-SCC在体内，2）定量四个NK受体Scatchard 分析，测量NK细胞毒性所需的可溶性配体浓度 和IFN-γ分泌，并测量NK细胞活化的动力学。 通过交联刺激和抑制的细胞毒性和细胞因子分泌 3）绘制LIR-I/IG和LIR-2/IG融合蛋白以及LIR- 1+ T 细胞识别HLA-B*0702变体，以检验所有抑制性HLA-B*0702变体的假设。 NK受体映射到类似的HLA位点，并可能导致引导NK的试剂 体内攻击这项工作结合了基础的体外研究和临床 调查这些研究是了解NK细胞如何 细胞识别并攻击患者中的OC-SCC。OC-SCC通常直接 可注射和局部应用细胞、细胞因子和药物 可以集中和加强朝鲜的攻击通过了解肿瘤配体和NK 受体信号，更好的预防和治疗OC-SCC可能会发展。

DESCRIPTION (Adapted from the Investigator's Abstract): Background: Oral cavity squamous cell carcinomas (OC-SCC) may be susceptible to NK cell surveillance, but little is known about the NK cell receptors and tumor cell ligands involved. Little or nothing is known about the NK receptor surface density, or their relative potency in triggering different effector functions. In contrast to KIR, the LIR- I and LIR-2 recognition epitopes on HLA class I molecules are not known. A unique panel of transformed NK cells mimic normal blood NK cells. Individual NK cells differentially respond to hematopoietic vs. OC-SCC cells, and to primary vs. metastatic autologous OC-SCC cells. OC-SCC cells stimulate NK IFN-gamma secretion via a combination cell surface ligands and IL-18, but not IL-12. Unlike T cells, NK activation by IL-18 does not require IL-12. NK cells are activated by immobilized or Fc receptor-bound anti-receptor mAb in dose-dependent and time-dependent fashions. LIR-I/Ig fusion protein binds selective HLA transfectants, suggesting inhibition by the E63-K66 salt bridge. The experimental plan of this proposal will 1A) search for distinct NK cell response patterns to OC-SCC cells and identify NK receptors and OC-SCC ligands that activate cytotoxicity and IFN-gamma secretion, 1B) characterize how OC-SCC IL-18 and cell surface ligands co-stimulate NK IFN-gamma secretion in primary and metastatic OC-SCC in vivo, 2) quantify four NK receptors by Scatchard analysis, measure the soluble ligand concentration required for NK cytotoxicity and IFN-gamma secretion, and measure the kinetics of activation of NK cytotoxicity and cytokine secretion by cross-linking stimulatory and inhibitory NK receptors, and 3) map how LIR-I/Ig and LIR-2/Ig fusion protein and LIR- 1+ T cells recognize HLA-B*0702 variants to test the hypothesis that all inhibitory NK receptors map to a similar HLA site and may lead to reagents that guide NK attack in vivo. This work combines basic in vitro research and clinical investigation. These studies are a necessary first step to understanding how NK cells recognize and attack OC-SCC in patients. OC-SCC is often directly accessible to injection and topical application of cells, cytokines, and drugs that may focus and augment NK attack. Via knowledge of tumor ligands and NK receptor signaling, better prevention and treatment of OC-SCC may be developed.