NK cell exhaustion in metastatic melanoma

转移性黑色素瘤中 NK 细胞耗竭

• 批准号: 9177359
• 负责人: Nina Bhardwaj
• 金额: $ 40.36万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-27 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9177359
• 关键词: Address; Adoptive Transfer; Advanced Malignant Neoplasm; Animals; Antibodies; Antigens; Biological Markers; Blood; CD80 gene; Cell physiology; Cells; Cellular biology; Clinical; Cytolysis; Cytotoxic T-Lymphocyte-Associated Protein 4; Defect; Development; Disease; Effector Cell; Equilibrium; Failure; Functional disorder; Growth; Human; Immune; Immune response; Immunity; Immunosuppression; In Vitro; Infiltration; Interferon Type II; Intervention; Ligands; Malignant Neoplasms; Melanoma Cell; Metastatic Melanoma; Modeling; Molecular; Mus; Natural Immunity; Natural Killer Cells; PDCD1LG1 gene; Participant; Patients; Phenotype; Phosphoric Monoester Hydrolases; Process; Production; Proliferating; Protein Dephosphorylation; Proteins; Receptor Activation; Receptor Signaling; Risk; Signal Transduction; Site; Staging; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-bet protein; Testing; Tumor Tissue; Virus Diseases; adaptive immunity; cancer therapy; cytokine; cytotoxic; exhaust; exhaustion; immunological synapse; in vivo; killings; melanoma; mouse model; peripheral blood; receptor; response; restoration; trafficking; tumor; tumor growth; tumor microenvironment; tumorigenesis

Project summary NK cells are key participants in the initial immune response to tumorigenesis and virus infections, equipped to respond rapidly through induction of cytokines and deployment of cytotoxic activity. A dynamic balance of positive and negative signals regulates NK cell target cell recognition and lysis, through engagement of a variety of activation and inhibitory receptors. However, as cancers advance there is accumulating evidence that NK cells become progressively dysfunctional. NK cell “exhaustion,” could explain the failure of NK cells to contain tumor growth in advanced cancers. While NK cell hyporesponsiveness has been described in various malignancies, there is little characterization of an “exhausted NK cell state” in metastatic disease, nor of the mechanisms that might underlie this phenotype. We now have evidence that NK cells progressively undergo exhaustion in late stage melanoma. Melanoma associated NK cells are characterized by a failure to proliferate, to produce interferon gamma (IFNγ) or to kill target cells. They (i) down regulate activation receptors, IL-2R subunits and NK cell regulatory transcription factors (T-bet, Eomes), (ii) upregulate inhibitory receptors and (iii) express high levels of the checkpoint molecule Tim-3, a phenotype that is consistent with “NK cell exhaustion”. Significantly, blockade of Tim-3 substantially reverses this phenotype and state of exhaustion in vitro (Can. Imm Res. 2014). Most strikingly however, we find that patients who have a clinical response to ipilimumab treatment spontaneously restore their NK cell function, despite the fact that these cells express little or no CTLA-4 (or PD-1 or PD-L1), possibly through reversal of tumor-associated systemic immune suppression. Characterizing NK cell dysfunction in melanoma, therefore, will be critical to understanding the modulation of NK cell biology in the tumor microenvironment (TME), and ultimately towards developing approaches that restore both innate and adaptive immunity, in vivo. Although the survival of advanced melanoma patients (stage IV) has been extended by interventions that reverse T cell exhaustion, we hypothesize that reversal of exhaustion in NK cells will contribute towards the full restoration of immune responses that are required to eliminate melanoma cells. To address this hypothesis, we aim to define the spectrum of NK cell exhaustion in melanoma and identify molecular/protein targets that potentiate NK cell exhaustion (Aim 1). Secondly, we will determine if NK cell exhaustion can be reversed in response to checkpoint blockade inhibition, and identify associated biomarkers (Aim 2). In Aim 3, we will develop murine models to define and test interventions that reverse NK cell exhaustion. Characterizing NK cell dysfunction in melanoma will be critical towards developing approaches that restore immunity, in vivo.

项目摘要 NK细胞是对肿瘤发生和病毒感染的初始免疫响应的关键参与者， 能够通过诱导细胞因子和细胞毒性活性的部署来迅速反应。动态 正面和负信号的平衡调节NK细胞靶细胞识别和裂解，通过 各种激活和抑制受体的参与。但是，随着癌症的发展 积累了NK细胞逐渐功能失调的证据。 NK细胞“疲惫”，可以解释 NK细胞未能在晚期癌症中含有肿瘤生长。而NK细胞的低调具有 我们在各种恶性肿瘤中被描述了，几乎没有表征的“疲惫的NK细胞状态” 转移性疾病，也是可能是这种表型基础的机制。我们现在有证据表明NK 细胞在晚期黑色素瘤中逐渐疲惫。黑色素瘤相关的NK细胞是 其特征是未能增殖，产生干扰素γ（IFNγ）或杀死靶细胞。他们（我）下来 调节激活受体，IL-2R亚基和NK细胞调节转录因子（T-BET，EOMES），（II） 上调抑制性受体，（iii）表达高水平的检查点TIM-3，一种表型，是一种表型 与“ NK细胞耗尽”一致。值得注意的是，TIM-3的封锁实质上逆转了这种表型 和体外疲惫状态（Can。Immres。2014）。但是，最引人注目的是，我们发现患者 对ipilimumab治疗的临床反应，从而恢复了其NK细胞功能，使命是 这些细胞很少或没有CTLA-4（或PD-1或PD-L1），通过肿瘤相关的逆转 全身免疫抑制。因此，表征黑色素瘤中NK细胞功能障碍对 了解肿瘤微环境（TME）中NK细胞生物学的调节，并最终朝向 正在开发体内恢复先天和适应性免疫学的方法。 尽管晚期黑色素瘤患者的生存率（IV期）已通过干预措施延长 这种反向T细胞疲劳，我们假设NK细胞疲惫的逆转将有助于 消除黑色素瘤细胞所需的免疫反应的完全恢复。解决这个问题 假设，我们旨在定义黑色素瘤中NK细胞耗尽的频谱并鉴定分子/蛋白质 靶向潜在的NK细胞耗尽（目标1）。其次，我们将确定NK细胞耗尽是否可以 响应检查点阻滞抑制并识别相关的生物标志物（AIM 2）。在AIM 3中， 我们将开发鼠模型来定义和测试干预措施，以逆转NK细胞的衰竭。特征 黑色素瘤中的NK细胞功能障碍对于开发体内恢复免疫力的方法至关重要。