ER stress pathways regulate T-cell allogeneic and anti-tumor responses

ER应激通路调节T细胞同种异体和抗肿瘤反应

• 批准号: 10577856
• 负责人: Xue-Zhong Yu
• 金额: $ 17.87万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10577856
• 关键词: ATF6 gene; Address; Allogenic; Antibodies; Antigen-Presenting Cells; Antigens; Antitumor Response; B-Lymphocytes; Biology; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Survival; Cells; Data; Degenerative Disorder; Dendritic Cells; Disease; Endoplasmic Reticulum; Environment; Exhibits; Foundations; Genetic Transcription; Goals; Health; Hematologic Neoplasms; Homeostasis; Human; Immune response; Immune system; Immunity; In Vitro; Inflammatory; Knock-out; Knowledge; Learning; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Metabolic Diseases; Mitochondria; Mus; Pathogenicity; Pathway interactions; Play; Proteins; Publishing; Regulation; Reporting; Role; Signal Transduction; Solid; Solid Neoplasm; Syngeneic Bone Marrow Transplantation; T cell response; T-Lymphocyte; Testing; antigen processing; cancer cell; cancer immunotherapy; chimeric antigen receptor T cells; conditional knockout; effector T cell; endoplasmic reticulum stress; exhaustion; experimental study; graft versus host disease induction; graft vs host disease; graft vs leukemia effect; improved; in vivo; leukemia; novel strategies; programs; protein misfolding; response; tumor; tumor microenvironment

Summary Unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress in response to protein misfolding. Three master regulators control the UPR: IRE1α, PERK, and ATF6. The primary goal of UPR is to induce transcriptional and translational programs to maintain ER homeostasis for cell survival. Thus, dysfunctional UPR signaling has been shown to contribute to various health conditions including metabolic diseases, degenerative diseases, inflammatory disorders, and cancer. The ER stress pathways have been studied in cancer cells extensively, but have been overall understudied in T-cell immunity and tolerance. There are several knowledge gaps in understanding the impacts of the ER stress pathways in T-cell immunity against cancer. Our long-term goal is to develop novel strategies through targeting the ER stress pathways for improving cancer immunotherapy of human malignancies. the overall objectives of this application are to provide critical information towards more understanding the impacts of ER stress pathways on immune responses against cancer, which will eventually help to fulfill our long-term goal. Our central hypothesis is that the IRE-1α/XBP-1 and PERK/CHOP pathways differentially regulate CD4 and CD8 anti-tumor responses in microenvironment dependent manner. The hypothesis has been formulated based on preliminary data generated from in vitro and in vivo experiments using genetically modified mice with T-cell conditional knock-out (KO) for XBP-1, PERK or both. This hypothesis will be tested in the following two Specific Aims: 1) To define the role of XBP-1 and PERK in T-cell mediated graft-versus-host (GVH) and graft- versus-leukemia (GVL) responses; 2) To define the impact of XBP-1 and PERK in T-cell immunity against tumor. The proposed study is expected to provide a strong guidance for improving T-cell based cancer immunotherapy by targeting the ER stress pathways and to provide a solid foundation for further studying underlying mechanisms of ER stress pathways in regulating T-cell immunity.

概括 未折叠蛋白反应（UPR）是一种高度保守的途径，允许细胞管理内质 响应蛋白质错误折叠的网状 (ER) 应激控制着 UPR：IRE1α、 PERK 和 ATF6 UPR 的主要目标是诱导转录和翻译程序维持。 因此，功能失调的 UPR 信号传导会导致多种细胞存活。 健康状况，包括代谢疾病、退行性疾病、炎症性疾病和癌症。 ER 应激途径主要在癌细胞中进行研究，但在 T 细胞免疫和耐受性在理解 ER 的影响方面存在一些知识差距。 我们的长期目标是通过研究 T 细胞免疫的应激途径来开发新的策略。 针对 ER 通路应激改善人类恶性肿瘤的整体免疫治疗。 此应用程序的目标是提供关键信息，以更好地了解 ER 的影响 抗癌免疫反应的压力途径，这最终将有助于实现我们的长期目标。 我们的中心假设是 IRE-1α/XBP-1 和 PERK/CHOP 途径差异调节 CD4 和 CD8 的抗肿瘤反应以微环境依赖的方式进行。 基于使用转基因小鼠进行的体外和体内实验产生的初步数据 XBP-1、PERK 或两者的 T 细胞条件敲除 (KO) 这一假设将在以下两个方面得到检验。 具体目标： 1) 明确 XBP-1 和 PERK 在 T 细胞介导的移植物抗宿主 (GVH) 和移植物抗宿主反应中的作用。 抗白血病 (GVL) 反应；2) 定义 XBP-1 和 PERK 对 T 细胞免疫的影响 拟议的研究有望为改善基于 T 细胞的癌症提供强有力的指导。 通过针对ER应激途径的免疫治疗，为进一步研究提供坚实的基础 ER 通路应激调节 T 细胞免疫的潜在机制。

项目成果

STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function.

STING 通过限制抗原呈递细胞功能来负调节同种异体 T 细胞反应。

• 发表时间: 2021-03
• 影响因子: 24.1
• 作者: Wu, Yongxia;Tang, Chih;Mealer, Corey;Bastian, David;Hanief Sofi, M;Tian, Linlu;Schutt, Steven;Choi, Hee;Ticer, Taylor;Zhang, Mengmeng;Sui, Xiaohui;Huang, Lei;Mellor, Andrew L;Hu, Chih;Yu, Xue
• 通讯作者: Yu, Xue