Defining the T-cell Response to Human Renal Cancer

定义 T 细胞对人类肾癌的反应

• 批准号: 7594768
• 负责人: James C Yang
• 金额: $ 125.24万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7594768
• 关键词: Allogenic; Antigens; Autologous; Autologous Dendritic Cells; CD4 Positive T Lymphocytes; CD8B1 gene; Cataloging; Catalogs; Cells; Class; Clinical; Clinical Trials; Cloning; Disease regression; HLA-A3 Antigen; Human; Immune; Immune response; Immune system; Immunotherapy; In Vitro; Laboratories; Lymphocyte; Lymphocyte Activation; Malignant Neoplasms; Malignant neoplasm of kidney; Methodology; Methods; Modeling; Nature; Patients; Proteins; Reagent; Renal Cell Carcinoma; Renal carcinoma; Role; System; T-Lymphocyte; Techniques; Tumor Antigens; Upper arm; base; cancer cell; cytokine; fibroblast growth factor-5; killings; melanoma; new technology; novel; response; tumor

Our laboratory is elucidating the nature of the immune response to tumors and establishing principles which may enhance our ability to immunize patients against known tumor antigens and induce tumor regression with cytokine or cell-transfer therapies. We have developed methodologies for identifying tumor-specific CTL from patients with renal cell cancer and successfully used these techniques to identify unmutated FGF-5 as an HLA-A3 restricted antigen on RCC, recognized by T-cells. This target protein has significant limitations on its clinical utility, such that the discovery of alternative tumor antigens is needed. Continuing these efforts looking at other antigens expressed on RCC, we have found tumor-reactive T-cells in patients with RCC which recognize their own tumors as well as allogeneic RCCs. Many of these cells are CD4 cells, recognizing antigens presented by HLA Class II molecules. The role and efficacy of tumor-reactive CD4+ cells in tumor rejection is still unclear. A more extensive catalog of such antigens will not only clarify our basic understanding of the role of CD4+ cells, but allow the recruitment of this other arm of the cellular immune response against cancer in novel immunotherapies. Renal cancer serves as a particularly useful model, because, unlike melanoma, the preponderance of tumor reactivity seems to reside in the CD4 compartment, yet this cancer is also quite susceptible to immunotherapies which can also treat melanoma (which is dominated by CD8 reactivity). We have developed a system of in vitro lymphocyte stimulation with autologous dendritic cells and autologous tumor which consistently generates tumor-reactive T-cells. We are adapting methods for cloning the antigens recognized to further our understanding of tumor recognition by CD4 cells.

我们的实验室正在阐明对肿瘤的免疫反应的性质，并建立可能增强我们免疫患者免受已知肿瘤抗原的能力并诱导细胞因子或细胞转移疗法诱导肿瘤消退的能力。我们已经开发了从肾脏细胞癌患者中鉴定出肿瘤特异性CTL的方法，并成功地使用了这些技术鉴定未经物质的FGF-5作为T细胞识别的RCC上的HLA-A3限制抗原。该靶蛋白对其临床实用性具有重大局限性，因此需要发现替代性肿瘤抗原。继续研究在RCC上表达的其他抗原的这些努力，我们发现RCC患者肿瘤反应性T细胞识别自己的肿瘤以及同种异体RCC。这些细胞中的许多是CD4细胞，识别由HLA II类分子呈现的抗原。肿瘤反应性CD4+细胞在肿瘤排斥中的作用和功效尚不清楚。此类抗原的更广泛的目录不仅可以阐明我们对CD4+细胞作用的基本理解，而且还可以募集新的免疫疗法中针对癌症的另一个细胞免疫反应。肾癌是一种特别有用的模型，因为与黑色素瘤不同，肿瘤反应性的优势似乎存在于CD4室中，但是该癌症也很容易受到可以治疗黑色素瘤的免疫疗法（由CD8反应性支配）。我们已经开发了一种体外淋巴细胞刺激的系统，并使用自体树突状细胞和自体肿瘤，该系统始终产生肿瘤反应性T细胞。我们正在调整克隆抗原的方法，以进一步了解CD4细胞对肿瘤识别的理解。