Autoimmune Mechanisms in the Response to Renal Cancer

描述(申请人提供)：这项研究建议是基于这样一个假设，即利用自身免疫机制来控制或杀死转移性肾细胞癌(RCC)，具有与自身免疫疾病相关的基因或生物学特征的RCC患者在接受免疫刺激药物治疗后更有可能获得良好的结果。这个项目是从我们发表的数据发展而来的，这些数据表明，携带两个自身免疫相关的HLA-II单倍型成分的IV期肾癌患者对细胞因子治疗的反应显著改善，并享有更长的生存时间。这一假设将使用从80名IV期肾癌患者的队列发展而来的HLAI和II型淋巴母细胞样细胞系(LCL)的银行集合进行验证，这些患者的结果涵盖了延长的无病生存期到肿瘤的快速进展和死亡。这些LCL将被用作这里描述的分子和遗传研究的DNA来源。本申请中提出的研究检查了肾癌预后与临床文献中提出的三种自体免疫机制之间的关系。第一个机制，在特定的目标1中进行了研究，表明肿瘤坏死因子α启动子的多态导致高表达的肿瘤坏死因子α驱动自身免疫性炎症过程。我们假设携带这些高表达基因的肾癌患者在免疫刺激治疗后有良好的预后。这将通过聚合酶链式反应和相关启动子区域的测序来解决。第二种机制在特定目标2中进行了研究，涉及补体成分C4a和C4b的缺陷，这两种成分在自身免疫性疾病患者中经常被观察到。我们认为C4a或C4b基因缺陷的肾癌患者预后良好。这一假设将通过分子分析和C4等位基因的定量来验证。第三种机制在具体目标3中涉及，它基于微嵌合的概念，即同种异体细胞在个人的循环或组织中的持久性。淋巴来源的微嵌合体细胞被认为是自身免疫组织破坏的媒介。我们假设携带微嵌合细胞的肾癌患者有良好的预后。实验采用HLACw基因分型法检测微嵌合体DNA，FISH/IHC法检测肿瘤浸润性微嵌合白细胞。这些数据将有助于临床预测肾癌患者的预后，以及了解宿主来源的肿瘤控制的基本机制。

DESCRIPTION (provided by applicant): This research proposal is based on the hypothesis that mechanisms of autoimmunity are utilized to control or kill metastatic renal cell carcinoma (RCC), and that RCC patients who have genotypic or biologic features associated with autoimmune disorders are more likely to have favorable outcomes after treatment with immune-stimulating drugs. This project evolves from our published data demonstrating that Stage IV RCC patients carrying components of two autoimmunity-associated HLA class II haplotypes have a significantly improved response to cytokine therapy and enjoy prolonged survival. The hypothesis will be examined using a banked collection of HLA Class I and II-typed lymphoblastoid cells lines (LCL) developed from a cohort of 80 Stage IV RCC patients whose outcomes span the spectrum of prolonged disease-free survival to rapid tumor progression and death. These LCL will be used as a source of DNA for the molecular and genetic studies described herein. The research proposed in this application examines the association of RCC outcomes with three purported mechanisms of autoimmunity put forth in the clinical literature. The first mechanism, examined in Specific Aim 1, suggests that polymorphisms of the tumor necrosis factor a promoter that lead to high TNFalpha expression drive autoimmune inflammatory processes. We hypothesize that RCC patients carrying these high-expression polymorphisms have favorable outcomes after immune stimulatory therapy. This will be addressed by PCR and sequencing of the involved promoter region. The second mechanism, examined in Specific Aim 2, involves deficiencies of the complement components C4A and C4B, which are frequently observed in patients with autoimmune disease. We propose that RCC patients with genetic deficiencies in C4A or C4B have favorable outcomes. This hypothesis will be examined by molecular analysis and quantitation of C4 alleles. The third mechanism, addressed in Specific Aim 3, is based on the concept of microchimerism, the persistence of allogeneic cells in the circulation or tissues of an individual. Microchimeric cells of lymphoid origin have been proposed to be mediators of autoimmune tissue destruction. We hypothesize that RCC patients who carry microchimeric cells have favorable outcomes. Experiments are designed to detect microchimeric DNA by HLA Cw genotyping, and tumor infiltrating microchimeric leukocytes by FISH/IHC. These data will be clinically useful in predicting outcomes of RCC patients, as well as in the understanding of basic mechanisms of host-derived tumor control.