PROTEOSOMES AND TUMOR IMMUNITY

描述（改编自申请人的摘要）：蛋白酶体是一种蛋白酶。 存在于胞质溶胶中的多亚基多催化蛋白酶复合物， 介导胞质抗原加工以产生肽， MHC I类呈递。 LMP2和7是受调节的亚单位， 存在于蛋白酶体的子集中。 它们似乎改变了蛋白酶体 增强细胞溶质MHC I抗原（Ag）加工的活性。 他们是 在某些细胞类型中组成型表达，表达受 其他细胞类型中的细胞因子。 研究人员假设， 肿瘤细胞中MHC I Ag加工途径的破坏导致 逃避免疫监视 本申请中描述的研究 将评估蛋白酶体LMP2和7在MHC I Ag中的作用， 加工并呈递给免疫系统， 免疫力 目的1分析新型二肽醛的作用 蛋白酶体抑制剂对常规MHC I Ag加工的影响。 目标2将使用 这些抑制剂，以评估蛋白酶体的贡献， 加工外源性Ags的机制。目标3将检验假设 LMP表达可能在肿瘤细胞中改变，导致肿瘤细胞 逃避免疫监视 这些研究应该提出机制， 增强对肿瘤的免疫应答并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.