NK CELL RECEPTOR RECOGNITION OF ORAL CANCERS

描述(改编自《调查者摘要》)：背景：口腔 鳞状细胞癌(OC-SCC)可能对NK细胞的监测敏感， 但对NK细胞受体和肿瘤细胞配体知之甚少。 牵涉其中。对NK受体表面密度知之甚少或一无所知 它们在触发不同效应器功能方面的相对效力。相比之下， 对于KIR，HLAI类分子上的LIR-I和LIR-2识别表位是 不知道。一组独特的转化的NK细胞模仿正常的血液NK细胞。 单个NK细胞对造血细胞和OC-SCC细胞的反应不同， 原代和转移性自体OC-SCC细胞。OC-SCC细胞刺激 通过细胞表面配体和IL-18的组合分泌NK干扰素-γ，但 不是IL-12。与T细胞不同，IL-18激活NK不需要IL-12。NK 细胞被固定化或Fc受体结合的抗受体单抗激活 剂量依赖和时间依赖的时尚。LIR-I/Ig融合蛋白结合 选择性的HLA转染体，提示受到E63-K66盐桥的抑制。 这项计划的实验计划是：1)寻找独特的自然杀伤细胞 OC-SCC细胞的应答模式及NK受体和OC-SCC配体的鉴定 激活细胞毒性和干扰素-γ的分泌，1B)表征OC-SCC IL-18和细胞表面配体共同刺激原代培养的NK细胞分泌干扰素 和体内转移的OC-SCC，2)用Scatchard方法定量检测四种NK受体 分析、测定NK细胞杀伤所需的可溶性配体浓度 和干扰素-γ的分泌，并测定NK细胞的激活动力学 交联型刺激和抑制的细胞毒性和细胞因子的分泌 NK受体；3)LIR-I/Ig和LIR-2/Ig融合蛋白与LIR-1+T的关系 细胞识别人类白细胞抗原-B*0702变异体以检验所有抑制性 NK受体映射到相似的HLA位点，并可能导致引导NK的试剂 活体内攻击。这项工作结合了基础体外研究和临床 调查。这些研究是了解NK细胞如何 细胞识别和攻击患者的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 这可能会集中和增强朝鲜的攻击。通过对肿瘤配体和NK的了解 受体信号转导，更好地预防和治疗OC-SCC可能会被开发出来。

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.