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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.

总结