ATF4 As A Driver of T Cell Inefficacy in Tumors

项目总结 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 对于肿瘤抗原的特异性，a-PD1免疫治疗的目的是重振PD-1+TIL以对抗固体 肿瘤。然而，PD-1高CD8+TIL的特点是终末衰竭和生物能量学明显差。 通过去极化的线粒体；因此，在各种肿瘤类型的癌症患者中，只有~20%的人对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、低氧和营养 应力集中导致CD8+T淋巴细胞终末耗竭。因此，识别编程的公共路径 对多种形式T细胞应激的反应可能为逆转TME介导的功能障碍提供一个有效的靶点 肿瘤抗原特异性人群的比例。我们的小组证明了CD8+TIL经历了持续的压力 通过慢性激活内质网(ER)应激感受器PKR ER样激酶(PERK)。津贴 在小鼠和人PD-1高CD8+TIL中，信号驱动CD8+TIL激活和代谢衰竭 抑制PERK诱导荷瘤小鼠对a-pd-1治疗的完全和长期反应。新的 绕过胰腺毒性的PERK抑制剂正在开发中，但第一代PERK抑制剂可诱导 由于急性反应丧失而对动物造成的毒性。家长研究计划的长期目标是 在慢性PERK轴上发现新的分子靶点，在实体瘤中CD8+TIL中发出细胞应激信号， 肉瘤患者对a-pd-1免疫治疗的限制性反应。补充项目的目标是 扩展初步数据，确定慢性兴奋靶向激活转录因子4(ATF4)激发 PD-1高CD8+TIL的细胞应激和功能障碍补充项目将检验以下中心假设 ATF4促进多发性肿瘤患者CD8+TIL的异常激活和耗竭以破坏T细胞功能 类型，限制对a-PD-1免疫治疗的反应。该项目直接与职业发展目标相一致 候选人Coral del Mar Alicea Pauneto，她的目标是在毕业时获得免疫肿瘤学方面的专业知识 努力实现她的长期目标，即增加获得尖端肿瘤免疫疗法的机会 少数族裔人口的代表性不足。

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.