Transcriptional Control of T Cell Function

T 细胞功能的转录控制

• 批准号: 10574535
• 负责人: JAMES SCOTT-BROWNE
• 金额: $ 41万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-22 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574535
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Animals; Antibodies; Antigens; Binding; Cancer Patient; Cell physiology; Cells; Chromatin; Chronic; Chronic Disease; Effector Cell; Failure; Family member; Foundations; Gene Expression; Genes; Genetic; Genetic Transcription; Human; Immunotherapy; Individual; Infection; Leucine Zippers; Link; Malignant Neoplasms; Modeling; Molecular; Mus; NR4A1 gene; NR4A2 gene; Nuclear Receptors; Outcome; Patients; Phenotype; Population; Production; Publishing; Regulatory Element; Resistance; Solid Neoplasm; T cell differentiation; T cell response; T cell therapy; T cell transcription factor 1; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Transcriptional Regulation; Translating; Virus Diseases; Work; acute infection; anti-tumor immune response; bZIP Domain; cancer therapy; candidate identification; chimeric antigen receptor; chimeric antigen receptor T cells; chronic infection; cofactor; cytokine; cytotoxic; engineered T cells; exhaust; exhaustion; experimental study; functional improvement; immune checkpoint blockade; improved; morphogens; neoplastic cell; novel; novel strategies; programs; receptor; receptor expression; response; small molecule; targeted treatment; transcription factor; tumor; tumor growth

PROJECT SUMMARY T cells responding to cancer develop a hyporesponsive phenotype, characterized by high levels of inhibitory receptor expression, low cytokine production, and a failure to control tumor growth. We have previously identified a transcriptional program induced by persistent antigen stimulation that was shared by mouse and human T cells responding to chronic viral infections and tumors. We linked this program to activation of the Nuclear Receptor Subfamily 4 Group A (NR4A) transcription factors (TFs), which are potently induced during chronic stimulation. We also identified NR4A-sensitive regulatory elements that became accessible in T cells responding to chronic viral infection and tumors. We found that NR4A TFs concomitantly promoted inhibitory receptor expression and limited cytokine production, leading to an exhausted T cell state that reduced chimeric antigen receptor expressing T (CAR-T) cell activity against solid tumors. CAR-T cells engineered to lack all three NR4A TFs differentiated to a unique population with potent anti-tumor activity compared to wild-type T cells. We connected this improved function to increased expression and activity of basic leucine zipper (bZIP) TFs in NR4A-deficient T cells than in wild-type. In new preliminary studies, we found that CAR-T cells with a partial loss of NR4A TFs also provided better protection than wild-type CAR-T cells, but had a unique “exhaustion resistant” phenotype that are poised for effector function and have increased potential for long term survival. In this application, we will test the hypothesis that NR4A and bZIP TFs can be “tuned” to control the transcriptional programs and function of “exhaustion resistant” CAR-T cells in tumors. In Aim 1, we will determine the impact of therapeutic interventions, using antibodies or small molecules, on the function and survival of “exhaustion resistant” CAR-T cells. In Aim 2, we will determine the contribution of NR4A regulated bZIP TFs to the function of NR4A-deficient CAR-T cells and their effects on transcriptional programs in “exhaustion resistant” CAR-T cells. In Aim 3, we will define the effects of NR4A TFs on bZIP TF activity at regulatory elements and identify chromatin associated co- factors that may be targeted to control the function of “exhaustion resistant” CAR-T cells. The expected outcome of our proposed studies is a comprehensive understanding of the effects of NR4A and bZIP TFs on CAR-T cells in tumors, through which we will identify practical strategies to “tune” the function of CAR-T cells for therapeutic benefit by controlling transcriptional programs.

项目概要 对癌症作出反应的 T 细胞会形成低反应表型，其特征是高水平的抑制 我们之前已经发现，受体表达、细胞因子产生低以及无法控制肿瘤生长。 由小鼠和人类 T 细胞共享的持续抗原刺激诱导的转录程序 我们将这个程序与核受体的激活联系起来。 亚科 4 A 组 (NR4A) 转录因子 (TF)，在慢性刺激过程中被有效诱导。 我们还鉴定了 NR4A 敏感的调节元件，这些元件可在响应慢性病的 T 细胞中使用。 我们发现 NR4A TF 同时促进抑制性受体表达和 细胞因子产生有限，导致 T 细胞处于耗尽状态，从而减少嵌合抗原受体 表达针对实体瘤的 T (CAR-T) 细胞活性，该细胞被设计为缺乏所有三种 NR4A TF。 与野生型 T 细胞相比，它们分化为具有强大抗肿瘤活性的独特群体。 这种改进的功能可增加 NR4A 缺陷中碱性亮氨酸拉链 (bZIP) 转录因子的表达和活性 在新的初步研究中，我们发现 CAR-T 细胞的 NR4A TF 部分缺失。 还提供了比野生型 CAR-T 细胞更好的保护，但具有独特的“抗衰竭”表型 在此应用中，我们准备发挥效应器功能并增加长期生存的潜力。 将测试 NR4A 和 bZIP TF 可以“调整”以控制转录程序的假设 “抗疲劳”CAR-T 细胞在肿瘤中的功能 在目标 1 中，我们将确定治疗的影响。 使用抗体或小分子对“抗疲劳”CAR-T 的功能和生存进行干预 在目标 2 中，我们将确定 NR4A 调节的 bZIP TF 对 NR4A 缺陷的功能的贡献。 CAR-T 细胞及其对“抗疲劳”CAR-T 细胞转录程序的影响 在目标 3 中，我们将。 定义 NR4A TF 对调节元件上的 bZIP TF 活性的影响，并确定染色质相关的共 可能有针对性地控制“抗疲劳”CAR-T 细胞功能的因素。 我们提出的研究的重点是全面了解 NR4A 和 bZIP TF 对 CAR-T 细胞的影响 在肿瘤中，我们将通过它确定实用的策略来“调整”CAR-T细胞的功能以进行治疗 通过控制转录程序受益。