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

基本信息

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
项目类别：
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

项目摘要

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.

概括展开的蛋白质反应（UPR）是一种高度保守的途径，允许细胞管理内质网状（ER）应力响应蛋白质错误折叠。三个主调节器控制UPR：IRE1α， PERK和ATF6。 UPR的主要目标是诱导转录和翻译程序以维护 ER稳态用于细胞生存。这就是功能失调的UPR信号传导有助于各种健康状况，包括代谢疾病，退化性疾病，炎症性疾病和癌症。 ER应力途径已在癌细胞中进行了广泛研究，但总体上已经了解了 T细胞免疫和耐受性。理解急诊室的影响有几个知识差距 T细胞免疫对癌症的应力途径。我们的长期目标是通过针对ER应力途径，以改善人类恶性肿瘤的癌症免疫疗法。总体本应用程序的目标是提供关键信息以更多地了解ER的影响针对癌症的免疫调查的压力途径，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途径对CD4和微环境依赖性方式的CD8抗肿瘤反应。该假设已提出基于从体外和体内实验产生的初步数据，使用一般修饰的小鼠与 XBP-1，PERK或两者的T细胞有条件敲除（KO）。该假设将在以下两个中进行检验具体目的：1）定义XBP-1和PERK在T细胞介导的移植物抗宿主（GVH）和移植物中的作用对抗 - 白血病（GVL）反应； 2）定义XBP-1和PERK在T细胞免疫中的影响瘤。拟议的研究预计将为改善基于T细胞的癌症提供强有力的指导通过靶向ER应力途径，并为进一步研究提供稳固的基础，免疫疗法 ER应力途径在调节T细胞免疫中的基本机制。