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: 10430505
• 负责人: Xue-Zhong Yu
• 金额: $ 21.88万
• 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/10430505
• 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; 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; base; cancer cell; cancer immunotherapy; chimeric antigen receptor T cells; conditional knockout; effector T cell; endoplasmic reticulum stress; exhaustion; experimental study; 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.

总结 未折叠蛋白反应（UPR）是一个高度保守的途径，允许细胞管理内质网 内质网（ER）应激反应蛋白质错误折叠。三个主调节器控制UPR：IRE 1 α， 还有ATF 6。UPR的主要目标是诱导转录和翻译程序，以维持 ER稳态对细胞存活的影响。因此，功能失调的UPR信号转导已被证明有助于各种 健康状况，包括代谢性疾病、退行性疾病、炎性疾病和癌症。 ER应激途径已在癌细胞中被广泛研究，但在癌症研究中总体上研究不足。 T细胞免疫力和耐受性。在理解ER的影响方面存在一些知识差距 T细胞抗肿瘤免疫中的应激途径。我们的长期目标是通过以下方式制定新策略 靶向ER应激途径以改善人类恶性肿瘤的癌症免疫疗法。整体 本应用程序的目标是提供关键信息，以更好地了解ER的影响 强调对抗癌症的免疫反应途径，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通路差异调节CD 4和CD 4 + T细胞， 以微环境依赖性方式的CD 8抗肿瘤应答。这个假设已经形成了 基于使用具有以下基因的转基因小鼠的体外和体内实验产生的初步数据， XBP-1、PERK或两者的T细胞条件性敲除（KO）。这一假设将在以下两个实验中得到检验： 具体目的：1）确定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（GVH）中的作用。 2）为了确定XBP-1和PERK在T细胞免疫中对抗白血病（GVL）应答的影响， 肿瘤这项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 通过靶向ER应激通路的免疫治疗，并为进一步研究提供坚实的基础 ER应激途径在调节T细胞免疫中的潜在机制。