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ATF4 As A Driver of T Cell Inefficacy in Tumors

ATF4 作为肿瘤 T 细胞无效的驱动因素

基本信息

批准号：
10799768
负责人：
Jessica E Thaxton
金额：
$ 8.72万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10799768
关键词：
Acute Animals Antigens Bioenergetics Bypass CD8B1 gene Cancer Patient Cell physiology Cellular Stress Chronic Data Development Distress Endoplasmic Reticulum Functional disorder Generations Goals Human Hypoxia Immunooncology Immunotherapy Mediating Mediator Metabolic Minority Groups Mitochondria Molecular Target Mus Nutrient Pancreas Parents Pathway interactions Patients Phosphotransferases Population Research Role Signal Transduction Solid Solid Neoplasm Specificity Stress T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Testing Toxic effect Tumor Antigens Underrepresented Minority Work activating transcription factor 4 anti-PD1 therapy biological adaptation to stress cancer infiltrating T cells cancer type career development coral endoplasmic reticulum stress exhaustion experience improved kinase inhibitor neoplasm immunotherapy programmed cell death protein 1 programs response sarcoma sensor stressor tumor

项目摘要

PROJECT SUMMARY Programmed cell death protein 1 (PD-1+) tumor infiltrating T cells (TILs) are a subset of T cells in tumors enriched for tumor antigen specificity, and a-PD1 immunotherapy aims to reinvigorate PD-1+ TILs to act against solid tumors. However, PD-1high CD8+ TILs are characterized by terminal exhaustion and poor bioenergetics marked by depolarized mitochondria; therefore, only ~20% of cancer patients across tumor types respond to a-PD-1 therapy, limiting ubiquitous FDA approvals. Multiple stressors such as persistent antigen, hypoxia, and nutrient stress converge to drive CD8+ TIL terminal exhaustion. Thus, identification of a common pathway that programs the response to multiple forms of T cell stress could provide a potent target to reverse TME-mediated dysfunction of the tumor-antigen specific population. Our group demonstrated that CD8+ TILs experience persistent stress through chronic activation of the endoplasmic reticulum (ER) stress sensor PKR ER-like kinase (PERK). PERK signaling drove CD8+ TIL activation and metabolic exhaustion in mouse and human PD-1high CD8+ TILs, and inhibition of PERK induced complete and long-term responses to a-PD-1 therapy in sarcoma bearing mice. New PERK inhibitors that bypass pancreatic toxicity are in development, but first-generation PERK inhibitors induce toxicity in animals due to loss of the acute response. The long-term goal of the parent research program is to identify new molecular targets in the chronic PERK axis that signal cell stress in CD8+ TILs in solid tumors, limiting response to a-PD-1 immunotherapy in sarcoma patients. The goal of the supplemental project is to expand preliminary data that identify that chronic PERK target activating transcription factor 4 (ATF4) instigates cell stress and dysfunction in PD-1high CD8+ TILs. The supplemental project will test the central hypothesis that ATF4 promotes aberrant activation and exhaustion in CD8+ TILs to undermine T cell function in multiple tumor types, limiting response to a-PD-1 immunotherapy. This project directly aligns with the career development goals of the candidate, Coral del Mar Alicea Pauneto, who aims to gain expertise in immune oncology in her graduate work to achieve her long-term goal of enhancing access to cutting-edge tumor immunotherapies for underrepresented minority populations.

项目摘要程序性细胞死亡蛋白1（PD-1+）肿瘤浸润性T细胞（TIL）是肿瘤中富集的T细胞亚群， α-PD 1免疫疗法旨在重振PD-1+ TIL，以对抗实体瘤。肿瘤的然而，PD-1high CD 8 + TILs的特征是末端耗竭和生物能量学显著降低，通过去极化的线粒体;因此，只有~20%的肿瘤类型的癌症患者对a-PD-1有反应治疗，限制无处不在的FDA批准。多种应激源，如持续抗原、缺氧和营养应激汇聚驱动CD 8 + TIL终末耗竭。因此，确定一个共同的途径，对多种形式T细胞应激的应答可以提供逆转TME介导的功能障碍的有效靶点肿瘤抗原特异性群体的。我们的研究小组证明，CD 8 + TILs经历持续的压力，通过内质网（ER）应激传感器PKR ER样激酶（PERK）的慢性激活。PERK 在小鼠和人PD-1高CD 8 + TIL中，信号传导驱动CD 8 + TIL活化和代谢衰竭， PERK的抑制在荷肉瘤小鼠中诱导对α-PD-1疗法的完全和长期应答。新绕过胰腺毒性的PERK抑制剂正在开发中，但第一代PERK抑制剂诱导由于急性反应丧失而对动物产生毒性。家长研究计划的长期目标是鉴定慢性PERK轴中的新分子靶点，其在实体瘤中的CD 8 + TIL中发出细胞应激信号，限制肉瘤患者对α-PD-1免疫疗法的应答。补充项目的目标是扩大初步数据，确定慢性PERK靶激活转录因子4（ATF 4）煽动 PD-1高CD 8 + TIL中的细胞应激和功能障碍。补充项目将检验中心假设， ATF 4促进CD 8 + TIL的异常活化和耗竭以破坏多发性肿瘤中的T细胞功能类型，限制对a-PD-1免疫疗法的反应。该项目直接符合职业发展目标候选人Coral德尔马尔Alicea Pauneto的目标是在毕业时获得免疫肿瘤学方面的专业知识。她致力于实现她的长期目标，即增加获得尖端肿瘤免疫疗法的机会，代表性不足的少数民族。