Mechanistic insights into immune suppression in brain tumors: a role for beta-arrestin 2

脑肿瘤免疫抑制的机制见解：β-arrestin 2 的作用

• 批准号: 10464968
• 负责人: Lucas Wachsmuth
• 金额: $ 5.18万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-09 至 2025-04-08
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464968
• 关键词: ARRB2; Acquired Immunodeficiency Syndrome; Adrenergic Receptor; B-Cell Activation; Bone Marrow; Brain; Brain Neoplasms; Breast Cancer Model; CD8-Positive T-Lymphocytes; Cancer Burden; Cell physiology; Cell surface; Cellular immunotherapy; Chronic; Data; Enhancers; Exhibits; Family; Gene Expression; Genes; Goals; Immune; Immune System Diseases; Immune system; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Impairment; Implant; In Vitro; Inflammation; Intervention; Intracranial Neoplasms; Knock-in; Knock-out; Knowledge; Lead; Licensing; Light; Link; Lymphoid; Lymphopenia; Malignant Neoplasms; Mediating; Membrane Proteins; Metastatic malignant neoplasm to brain; Mission; Mus; Nuclear; Pathology; Patients; Phenotype; Play; Primary Brain Neoplasms; Prognosis; Proteins; Public Health; Role; Signal Transduction; Solid Neoplasm; Sphingosine-1-Phosphate Receptor; Surface; Sympathetic Nervous System; T-Lymphocyte; Therapeutic; Tumor Immunity; Wild Type Mouse; Work; anti-tumor immune response; arrestin 2; beta-2 Adrenergic Receptors; beta-arrestin; cancer therapy; immune depression; improved; in vivo; in vivo Model; inhibitor; insight; lymphoid organ; neoplastic cell; novel; prevent; protein function; receptor; success; transcription factor; tumor

ABSTRACT Cancers located within the brain, including both primary brain tumors and metastases, exhibit dismal prognoses and do not respond well to immunotherapy, in part due to marked systemic tumor-induced immunosuppression. Systemic immune suppression is a hallmark of IC tumors, independent of tumor type. Systemic immune deficiencies in patients and mice with IC tumors include AIDS-level lymphopenia, lymphoid organ contraction, and sequestration of T cells in the bone marrow (BM). BM T cell sequestration follows the loss of T cell sphingosine-1-phosphate receptor 1 (S1P1), a surface protein that functions as an “exit visa” mediating T cell egress from lymphoid organs. Surface levels of S1P1 can be stabilized by knocking out (KO) β-arrestin 2 (βarr2), the protein responsible for S1P1 internalization. Unexpectedly, βarr2KO mice implanted with IC tumors demonstrate an unprecedented ~50-80% long-term survival benefit in the absence of any additional intervention. Both CD4+ and CD8+ T cells are required for this enhanced survival, and T cell activating therapies further extend βarr2KO survival. These data suggest that βarr2KO mice mount an enhanced T cell anti-tumor immune response in βarr2KO mice, although the mechanism of enhanced T cell function remains unclear. For T cells to mount an effective anti-tumor immune response and clear tumors in vivo, they must activate Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB). NF-κB functions as a “master regulator” of inflammation, and βarr2 is a known inhibitor of NF-κB activation. Importantly, this βarr2-NF-κB axis is regulated by the sympathetic nervous system (SNS), specifically through the beta-2 adrenergic receptor (β2AR). SNS signaling through the β2AR increases βarr2 levels and thereby prevents NF-κB activation. SNS overactivation in other IC pathologies has been linked to the same systemic immune deficits seen with IC tumors, and we have evidence of increased SNS signaling in IC tumor-bearing mice. Notably, βarr2KO tumor- bearing mice exhibit less lymphopenia and lymphoid organ contraction. Furthermore, SNS blockade abrogates BM T cell sequestration in tumor-bearing wild-type (WT) mice. Taken together, these findings suggest that 1) βarr2 plays a key role in restricting anti-tumor immune responses by inhibiting NF-κB, and 2) SNS overactivation due to IC tumors may drive increased immunosuppressive βarr2 activity. The long-term goal of this proposal is to generate mechanistic insights into tumor-driven immunosuppression that will inform therapeutic approaches to license and improve immunotherapies. The primary objectives of this proposal are to determine the impact of 1. βarr2 deficiency on anti-tumor T cell function and 2. IC tumor- driven SNS overactivation on βarr2 activity and anti-tumor immunity.

摘要 位于脑内的癌症，包括原发性脑肿瘤和转移瘤， 免疫治疗效果不佳，部分原因是由于明显的全身性肿瘤诱导的免疫反应。 免疫抑制全身免疫抑制是IC肿瘤的标志，与肿瘤类型无关。 患有IC肿瘤的患者和小鼠中的全身免疫缺陷包括AIDS水平的淋巴细胞减少症、淋巴细胞减少症和淋巴细胞减少症。 器官收缩和骨髓（BM）中T细胞的隔离。BM T细胞隔离遵循 T细胞鞘氨醇-1-磷酸受体1（S1 P1）的缺失，S1 P1是一种表面蛋白，其功能是“出境签证” 介导T细胞从淋巴器官排出。S1 P1的表面水平可以通过敲除（KO）来稳定 β-arrestin 2（β arr 2），负责S1 P1内化的蛋白质。出乎意料的是，β arr 2KO小鼠植入 IC肿瘤显示出前所未有的~50-80%的长期生存益处， 额外干预。这种增强的存活需要CD 4+和CD 8 + T细胞，并且T细胞 活化疗法进一步延长β arr 2KO存活。这些数据表明，β arr 2KO小鼠在小鼠体内能够产生一种 增强β arr 2KO小鼠的T细胞抗肿瘤免疫应答，尽管增强T细胞抗肿瘤免疫应答的机制是通过增强β arr 2KO小鼠的T细胞免疫应答来实现的，但是， 功能尚不清楚。 为了使T细胞在体内产生有效的抗肿瘤免疫应答并清除肿瘤，它们必须激活 活化B细胞（NF-κB）的核因子κ轻链增强子。NF-κB作为“主核”发挥作用 β arr 2是已知的NF-κB活化抑制剂。重要的是，这种β arr 2-NF-κB 轴由交感神经系统（SNS）调节，特别是通过β-2肾上腺素能受体 （β 2 AR）。通过β 2 AR的SNS信号传导增加β arr 2水平，从而阻止NF-κB活化。SNS 在其他IC病理中的过度激活与IC中所见的相同的全身免疫缺陷有关 肿瘤，我们有证据表明，增加SNS信号在IC荷瘤小鼠。值得注意的是，β arr 2KO肿瘤- 荷瘤小鼠表现出较少的淋巴细胞减少和淋巴器官收缩。此外，SNS封锁废除了 携带肿瘤的野生型（WT）小鼠中的BM T细胞隔离。综上所述，这些发现表明：1） β arr 2通过抑制NF-κB在抑制抗肿瘤免疫反应中起关键作用，和2）SNS 由于IC肿瘤引起的过度活化可能会导致免疫抑制性β arr 2活性增加。 这项提案的长期目标是产生对肿瘤驱动的免疫抑制机制的见解 这将为许可和改进免疫疗法的治疗方法提供信息。本项目的主要目标 建议是确定1的影响。β arr 2缺陷对抗肿瘤T细胞功能的影响; 2. IC肿瘤- 驱动SNS过度激活对β arr 2活性和抗肿瘤免疫的影响。