MHC Class II Antigen Processing and Immune Recognition of Melanoma

描述(由申请人提供)：黑色素瘤是最致命的皮肤癌形式，对现有的化疗药物具有抗药性。免疫疗法在治疗转移性黑色素瘤方面有很大的前景，因为黑色素瘤抗原已经被识别出来，患者可以产生针对这些抗原的T和B细胞反应，在某些情况下会导致自发缓解。有效的免疫治疗需要肿瘤抗原在MHC-II类的背景下被提呈，以激活CD4T淋巴细胞，以产生和维持抗肿瘤免疫反应。此外，由于许多黑色素瘤抗原代表良性黑素细胞中存在的自身抗原，有效的抗肿瘤反应需要避免抑制对自身抗原的免疫反应的耐受机制。我们建议解决MHC II类抗原处理组件，特别是伽马干扰素诱导的溶酶体硫醇还原酶(GILT)在黑色素瘤的免疫识别中的作用。黑色素瘤抗原包括酪氨酸酶、酪氨酸酶相关蛋白(TRP)-1、Trp-2和gplOO可能是GILT减少溶酶体的底物，因为这些黑素体膜蛋白存在于MHC II类负荷室中，并含有内部二硫键。我们已经证明了GILT在体外对TRP-1的MHC II类加工是必不可少的。在这项建议中，我们计划利用Trp-1特异性T细胞受体转基因小鼠模型来探索GILT在对Trp-1耐受发展中的作用。我们接下来计划确定GILT在酪氨酸酶、Trp-1、Trp-2和gplOO的整体免疫反应中的作用，并通过比较GILT缺陷小鼠与野生型小鼠品系的体内免疫反应来评估GILT在保护黑色素瘤攻击中的作用。为了探索与人类疾病的相关性，我们将检测GILT在人类黑色素瘤中的表达。这些研究将确定对黑色素瘤产生免疫反应所需的抗原处理的关键特征，并可能有助于理解导致免疫逃避的机制。这些研究的长期目标是帮助开发有效的黑色素瘤免疫疗法。

DESCRIPTION (provided by applicant): Melanoma is the most lethal form of skin cancer and is resistant to existing chemotherapeutic agents. Immunotherapy holds great promise in the treatment of metastatic melanoma because melanoma antigens have been identified and patients generate T and B cell responses specific for these antigens which in some cases lead to spontaneous remission. Effective immunotherapy requires presentation of tumor antigens in the context of MHC class II for the activation of CD4+ T lymphocytes to generate and sustain the anti-tumor immune response. Additionally, since many melanoma antigens represent self-antigens present in benign melanocytes, a productive anti-tumor response requires the avoidance of tolerance mechanisms which suppress the immune response to self-antigens. We propose to address the role of MHC class II antigen processing components, in particular gamma-interferon inducible lysosomal thiol reductase (GILT), in the immune recognition of melanoma. Melanoma antigens including tyrosinase, tyrosinase-related protein (TRP)-1, TRP-2 and gplOO are likely to be substrates for lysosomal reduction by GILT, because these melanosomal membrane proteins are present in the MHC class II loading compartment and contain internal disulfide bonds. We have demonstrated that GILT is essential for the MHC class II processing of TRP-1 in vitro. In this proposal, we plan to explore the role of GILT in the development of tolerance to TRP-1 using a TRP-1-specific T cell receptor transgenic mouse model. We next plan to determine the role of GILT in the overall immune response to tyrosinase, TRP-1, TRP-2 and gplOO and to evaluate the role of GILT in protection from melanoma challenge by comparing in vivo immune responses in GILT-deficient compared to wild-type mouse strains. To explore the relevance in human disease, we will determine the expression of GILT in human melanoma. These studies will identify key features of antigen processing required to generate an immune response to melanoma and may aid in the understanding of mechanisms that lead to immune evasion. The long-term goal of these studies is to aid the development of effective immunotherapy for melanoma.