Impact of senescence on T-cell function and immunotherapeutic response

衰老对 T 细胞功能和免疫治疗反应的影响

• 批准号: 10460605
• 负责人: Christin E Burd
• 金额: $ 42.12万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460605
• 关键词: Ablation; Activities of Daily Living; Advanced Malignant Neoplasm; Age; Age of Onset; Aging; Antibody Therapy; Antigens; Autoimmune; Biological; Biological Aging; Biological Markers; Biological Process; CDKN2A gene; Cell Aging; Cell Cycle; Cell physiology; Cells; Cellular biology; Chronic Disease; Chronology; Clinical; Custom; Data; Disease; Epigenetic Process; Event; Failure; Functional disorder; Human; Immune; Immune checkpoint inhibitor; Immunization; Immunologics; Immunotherapeutic agent; Immunotherapy; Knockout Mice; Life Experience; Ligands; Longevity; Malignant Neoplasms; Measures; Mediating; Messenger RNA; Metastatic Melanoma; Modeling; Molecular; Mus; Newly Diagnosed; Outcome; Pathology; Patients; Pharmaceutical Preparations; Physiological; Physiological Processes; Pilot Projects; Process; Property; Reaction; Receptor Activation; Receptor Signaling; Regimen; Reporter; Research; Risk Factors; Role; Schedule; Surface; Surrogate Markers; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Tumor Suppressor Proteins; Up-Regulation; Work; age related; anti-tumor immune response; cancer diagnosis; cancer immunotherapy; cell type; checkpoint therapy; combat; conditional knockout; design; exhaust; exhaustion; fitness; functional restoration; immune checkpoint; improved; innovation; innovative technologies; melanoma; mouse model; nano-string; neoplastic cell; novel; outcome prediction; peripheral blood; pre-clinical; predictive marker; prevent; receptor; response; senescence; study population; success; tumor

ABSTRACT Senescent cells, marked by persistent p16INK4a expression, increase in aging tissues and promote the onset of age-related disease in mice. These observations have led to widespread pre-clinical and clinical use of p16INK4a as a surrogate marker of declining biological function. However, the age-related molecular events that cause p16INK4a levels to rise are largely undefined and studies have yet to determine if senescent cells retain any normal physiological functions. Using an innovative technique to simultaneously profile mRNAs indicative of T-cell subtype, function and cellular senescence, we find that p16INK4a levels rise in parallel with markers of T-cell exhaustion. Exhaustion is a progressive form of T-cell dysfunction catalyzed by repeated immune stimulation. Exhausted T-cells express inhibitory receptors that oppose T-cell receptor (TCR) signaling when activated by exogenous ligands. Current and emerging cancer immunotherapies block these receptor-ligand interactions, known as immune checkpoints, to restore the function of tumor-specific T-cells. We observe that the expression of p16INK4a in peripheral blood T-lymphocytes (PBTLs) from newly diagnosed melanoma patients is age-independent and appears to predict immunotherapeutic discontinuation. These findings support our overarching hypothesis that T-cell senescence is a consequence of continued antigenic stimulation and dictates the outcome of immune checkpoint inhibitor therapy in melanoma. We propose a model wherein initial T-cell stimulation leads to the transient upregulation of both p16INK4a and markers of T-cell exhaustion. However, when the TCR is repeatedly engaged, sustained p16INK4a expression drives entry into cellular senescence, thereby locking T-cells into a non- proliferative state in which immunotherapies can no longer provide benefit to the patient. The proposed studies will determine the chronologic, molecular and functional relationship between T-cell exhaustion and cellular senescence (Aim 1A, C), identify the physiological processes that regulate p16INK4a downstream of TCR activation (Aim 1B) and define the impact of T-cell senescence in immune checkpoint inhibitor therapy (Aim 2). This work will delineate the physiological events that trigger T-cell senescence and establish the identity and functional capacity of these cells, which are increasingly used as a surrogate measure of biological aging. These studies are also likely to advance cancer immunotherapy regimens by demonstrating that a circulating peripheral blood marker could be used to predict outcome, improve response rates and minimize toxicity.

抽象的 以持续的P16INK4A表达为特征的衰老细胞增加，增加衰老组织并促进 小鼠与年龄有关的疾病。这些观察结果导致了p16ink4a的广泛临床和临床使用 作为生物学功能下降的替代标志。但是，导致年龄相关的分子事件 P16INK4A的升高水平在很大程度上不确定，研究尚未确定衰老细胞是否保留任何正常 生理功能。 使用创新的技术同时介绍MRNA，指示T细胞亚型，功能和细胞 衰老，我们发现P16INK4A水平与T细胞耗尽的标记并行上升。疲惫是一个 通过反复的免疫刺激催化的T细胞功能障碍的进行性形式。耗尽的T细胞表达 当外源配体激活时，会反对T细胞受体（TCR）信号传导的抑制受体。当前的 新兴的癌症免疫疗法阻止了这些受体 - 配体相互作用，称为免疫检查点， 恢复肿瘤特异性T细胞的功能。我们观察到外周血中p16ink4a的表达 来自新诊断的黑色素瘤患者的T淋巴细胞（PBTL）是不依赖年龄的，似乎可以预测 免疫治疗中断。这些发现支持了我们的总体假设，即T细胞衰老 是持续抗原刺激的结果，并决定了免疫检查点的结果 黑色素瘤抑制剂疗法。我们提出了一个模型，其中初始T细胞刺激导致瞬态 P16INK4A和T细胞耗尽标记的上调。但是，当TCR反复参与时， 持续的P16INK4A表达驱动进入细胞衰老，从而将T细胞锁定在非 - 免疫疗法无法再为患者提供好处的增生状态。提出的研究 将确定T细胞疲惫与细胞之间的时间顺序，分子和功能关系 衰老（AIM 1A，C），确定调节TCR下游P16INK4A的生理过程 激活（AIM 1B）并定义了T细胞衰老在免疫检查点抑制剂治疗中的影响（AIM 2）。 这项工作将描述触发T细胞衰老的生理事件，并确定身份和 这些细胞的功能能力越来越多地用作生物衰老的替代度量。这些 研究还可能通过证明循环周围来推动癌症免疫疗法方案 血液标记物可用于预测结果，提高反应率并最大程度地减少毒性。