Autoimmune Mechanisms in the Response to Renal Cancer

描述（由申请人提供）：本研究计划基于自身免疫机制被用于控制或杀死转移性肾细胞癌（RCC）的假设，并且具有与自身免疫性疾病相关的基因型或生物学特征的RCC患者在使用免疫刺激药物治疗后更有可能获得良好的结果。该项目源于我们发表的数据，该数据表明，携带两种自身免疫相关HLA II类单倍型成分的IV期RCC患者对细胞因子治疗的反应显著改善，生存期延长。该假设将通过从80例IV期RCC患者中收集的HLA I类和ii型淋巴母细胞样细胞系（LCL）进行检验，这些患者的结局跨越了延长无病生存期到快速肿瘤进展和死亡的范围。这些LCL将用作本文所述分子和遗传研究的DNA来源。本申请中提出的研究探讨了临床文献中提出的三种自称的自身免疫机制与RCC结果的关联。第一种机制，在Specific Aim 1中研究，表明肿瘤坏死因子（一种导致高tnf α表达的启动子）的多态性驱动自身免疫炎症过程。我们假设携带这些高表达多态性的RCC患者在免疫刺激治疗后具有良好的预后。这将通过PCR和相关启动子区域的测序来解决。第二种机制，在Specific Aim 2中研究，涉及补体成分C4A和C4B的缺乏，这在自身免疫性疾病患者中经常观察到。我们认为C4A或C4B基因缺陷的RCC患者预后良好。这一假设将通过C4等位基因的分子分析和定量来检验。第三种机制是基于微嵌合（microchimerism）的概念，即同种异体细胞在个体循环或组织中的持久性。淋巴细胞起源的嵌合细胞被认为是自身免疫组织破坏的介质。我们假设携带嵌合细胞的RCC患者有良好的预后。采用HLA - Cw基因分型检测微嵌合DNA， FISH/IHC检测肿瘤浸润性微嵌合白细胞。这些数据将在临床上用于预测RCC患者的预后，以及了解宿主源性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.