PROTEOSOMES AND TUMOR IMMUNITY

描述(改编自申请人的摘要)：蛋白酶体是一种 胞浆中存在多亚单位多催化酶复合体 被提议用来调节胞浆抗原的处理以产生多肽 MHC I类报告。LMP2和LMP7是受调控的亚单位 存在于蛋白酶体的一个子集中。它们似乎改变了蛋白酶体 增强胞浆MHC I抗原(Ag)处理的活性。他们是 在某些细胞类型中组成性表达，并且表达受 其他细胞类型中的细胞因子。调查人员假设 肿瘤细胞中MHC I Ag处理途径的中断导致 逃避免疫监视。本申请表中描述的研究 将评估蛋白酶体LMP2和7在MHC I Ag中的作用 产生抗肿瘤的处理和呈递给免疫系统 豁免权。目的1分析新型二肽醛的作用。 蛋白酶体抑制剂在常规MHC-I-Ag加工中的应用。AIM 2将使用 这些抑制剂用来评估蛋白酶体对替代的贡献 外源AGS的加工机制。目标3将检验这一假设 LMP在肿瘤细胞中的表达可能会改变，从而导致肿瘤细胞 逃避免疫监视。这些研究应该提出机制，以 增强对肿瘤的免疫反应，促进癌症的免疫治疗。

DESCRIPTION (Adapted from the Applicant's Abstract): The proteasome is a multi-subunit multi-catalytic protease complex present in the cytosol that is proposed to mediate cytosolic antigen processing to produce peptides for MHC class I presentation. LMP2 and 7 are regulated subunits that are present in a subset of proteasomes. They appear to alter proteasome activity to enhance cytosolic MHC I antigen (Ag) processing. They are constitutively expressed in some cell types, and expression is regulated by cytokines in other cell types. The investigators hypothesize that disruption of the MHC I Ag processing pathway in tumor cells results in escape from immune surveillance. The studies described in this application will evaluate the contribution of proteasomes, LMP2 and 7, in MHC I Ag processing and presentation to the immune system for generating antitumor immunity. Aim 1 will analyze the effects of novel dipeptide aldehyde proteasome inhibitors on conventional MHC I Ag processing. Aim 2 will use these inhibitors to assess the contribution of proteasomes to alternative mechanisms for processing of exogenous Ags. Aim 3 will test the hypothesis that LMP expression may be altered in tumor cells, resulting in tumor cell escape from immune surveillance. These studies should suggest mechanisms to enhance immune responses to tumors and facilitate immunotherapy of cancer.