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.

抽象的 位于大脑内的癌症，包括原发性脑肿瘤和转移，暴露于 预后，对免疫疗法的反应不佳，部分原因是系统性肿瘤引起的明显 免疫抑制。全身免疫抑制是与肿瘤类型无关的IC肿瘤的标志。 患有IC肿瘤的患者和小鼠的全身免疫缺陷包括艾滋病级淋巴细胞减少症，淋巴样 器官收缩，以及骨髓（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（S1P1）的丧失，该表面蛋白充当“出口签证” 介导T细胞从淋巴机构出口。 S1P1的表面水平可以通过敲出（KO）来稳定 β-arrestin 2（βArr2），该蛋白质负责S1P1内在化。出乎意料的是，βarr2KO小鼠植入了 与IC肿瘤一起表现出史无前例的〜50-80％的长期生存益处 其他干预措施。这种增强的存活需要CD4+和CD8+ T细胞，T细胞都需要 激活疗法进一步扩展了βarr2KO的存活。这些数据表明βarr2KO小鼠安装 增强的T细胞抗肿瘤免疫响应在βarr2KO小鼠中，尽管增强的T细胞的机制 功能尚不清楚。 为了使T细胞在体内安装有效的抗肿瘤免疫反应和清除肿瘤，它们必须激活 活化B细胞（NF-κB）的核因子kappa-light链增强剂。 NF-κB充当“主人 βarr2是已知的NF-κB激活抑制剂。重要的是，该βArr2-NF-κB 轴由交感神经系统（SNS）调节，特别是通过Beta-2肾上腺素接收器调节 （β2AR）。 SNS信号通过β2AR增加了βARR2水平，从而防止NF-κB激活。 SNS 在其他IC病理中过度活化已与相同的系统性免疫相关 肿瘤，我们有证据表明，在含有IC肿瘤的小鼠中，社交媒体信号增加了。值得注意的是，βarr2ko肿瘤 - 轴承小鼠暴露了较少的淋巴细胞减少和淋巴器官收缩。此外，社交媒体封锁废除 BM T细胞固相中的肿瘤野生型（WT）小鼠。综上所述，这些发现表明1） βARR2通过抑制NF-κB限制抗肿瘤免疫复杂和2）SNS起着关键作用 由于IC肿瘤引起的过度激活可能会促进免疫抑制βARR2活性增加。 该提案的长期目标是生成对肿瘤驱动免疫抑制的机械见解 这将为理论方法提供许可和改善免疫疗法的方法。这个的主要目标 提案是确定1。βArr2缺乏对抗肿瘤T细胞功能的影响和2。 驱动的SN在βARR2活性和抗肿瘤免疫力上过度活化。