The role of CD4+ T cells in melanoma immunotherapy

职位描述(申请人提供)：应聘者为近期晋升人员 研究助理教授，他一直在研究树突状细胞的使用 细胞激活CD8+T细胞对黑色素瘤的反应 V·恩格尔哈德博士。作为走向独立的一部分，候选人是 发展他自己的研究项目，从他的博士后推断 调查。候选人的意图是将特敏奖作为一种 在导师的指导下智力和科学进步的基础 由恩格尔哈德博士提供，随后成功过渡到完全 肿瘤免疫治疗方面的独立研究。弗吉尼亚大学 为本提案提供了理想的环境，这是由于 基础科学教师和与医生合作的潜力 对在临床环境中应用免疫疗法感兴趣。这项研究 该提案是基于几个小组的累积数据提出的 CD4+T细胞在引导适应性免疫反应中起着不可或缺的作用 通过为专业抗原提供激活刺激来对抗肿瘤 呈递细胞、细胞因子支持产生效应器和记忆性CD8+ T细胞和直接抗肿瘤活性。因此，接种疫苗 诱导CD8+T细胞和CD4+T细胞对肿瘤的反应的方案是 可能比那些针对适应性武器的任何一只手臂的武器更有效 单独的免疫反应。基于一种假设，即CD4+T细胞的产生 能够对MHC II类限制性表位做出特异性反应的细胞 从黑素细胞中提取的分化蛋白会促进生成 肿瘤特异性CD8+T细胞反应和记忆性CD8+T细胞的产生 抗黑色素瘤细胞，我们建议：1.鉴定和比较人类白细胞抗原-DR*0401- 树突状细胞上酪氨酸酶衍生的限制性多肽 细胞、黑色素瘤细胞或两者兼而有之。2.描述CD4+T细胞对 DR4/IED转基因小鼠酪氨酸酶衍生的人类白细胞抗原-DR*0401限制性多肽 在外周表达或不表达酪氨酸酶。3.定义 酪氨酸酶特异性CD_4~+T细胞及其表位在免疫原代中的作用 酪氨酸酶特异性CD8+T细胞和抗黑色素瘤反应。结果是 从这项提案派生出来的，预计将对我们的 对外周表达自身抗原的免疫应答的理解 与黑色素瘤相关，免疫治疗的设计 针对黑色素瘤的干预。

DESCRIPTION (provided by applicant): The candidate is a recently promoted Research Assistant Professor who has been investigating the use of dendritic cells to activate CD8+ T cell responses against melanoma in the laboratory of Dr. V. Engelhard. As part of a move towards independence, the candidate is developing his own research project that extrapolates from his postdoctoral investigations. It is the candidate's intention to use the Temin Award as a foundation to advance intellectually and scientifically under the mentorship provided by Dr. Engelhard, followed by a successful transition to completely independent research in tumor immunotherapy. The University of Virginia provides an ideal environment for this proposal due to the excellence of the basic science faculty and the potential for collaboration with physicians interested in applying immunotherapy in a clinical setting. The research proposal is based on the accumulated data from several groups that suggests that CD4+ T cells play an integral role in directing adaptive immune responses against tumors, by providing activation stimuli for professional antigen presenting cells, cytokine support the generation of effector and memory CD8+ T cells and direct anti-tumoricidal activity. Therefore, vaccination protocols that elicit CD8+ T cell and CD4+ T cell responses against tumors are likely to be more effective than those that target either arm of the adaptive immune response alone. Based on the hypothesis that the generation of CD4+ T cells that can respond specifically to MHC class II-restricted epitopes derived from melanocyte differentiation proteins will enhance the generation of tumor-specific CD8+ T cell responses, and the generation of memory CD8+ T cells against melanoma, we propose to: 1. Identify and compare HLA-DR*0401- restricted peptides derived from tyrosinase that are presented on dendritic cells, melanoma cells, or both. 2. Characterize the CD4+ T cell response to tyrosinase-derived HLA-DR*0401-restricted peptides in DR4/IEd transgenic mice that either do or do not express tyrosinase in the periphery. 3. Define the role of tyrosinase-specific CD4+ T cells and their epitopes in the generation of tyrosinase-specific CD8+ T cells and anti-melanoma responses. The results derived from this proposal are expected to have immediate impact on our understanding of the immune response to peripherally expressed self-antigens t h a t are relevant to melanoma, and the design of immunotherapeutic interventions against melanoma.