Immune Aging in Responsiveness to Checkpoint Blockade Immunotherapies

衰老对免疫力有着深远的影响（免疫衰老），有报道称， 癌症和感染，疫苗效力降低，对持续感染的免疫力减弱， 年龄增长。尽管如此，令人惊讶的是，人们对癌症免疫和免疫疗法 结果会随着免疫老化而改变。 SEER计划（监测流行病学最终结果，https://seer.cancer.gov）估计大约 38.4%的男性和女性会在一生中的某个时候被诊断出患有癌症。在面对 这些令人震惊的统计数据，过去十年已经预示着显着的新的免疫为基础的治疗与有效的临床 功效FDA批准的一线治疗-使用抗体的检查点阻断免疫疗法（CBI）， 阻断T细胞反应的显性负调节因子PD-1或PD-L1-已被证明是一种真实的杰作 治疗几种难治性实体瘤（如RCC、NSCLC、MCC和黑素瘤）。然而，并非所有患者 在对PD-1 CBI有反应的患者中，反应性的程度是可变的，并且预测治疗效果的生物标志物 有效性在很大程度上仍然难以捉摸。这个项目的目标是解开免疫代谢机制 这是PD-1 CBI的广泛不同功效的基础，具有“免疫老化”。 基于几个记录的免疫缺陷随着年龄的增长，我们预测PD-1 CBI的治疗效果 可能会随着年龄的增长而受损事实上，我们实验室和其他实验室最近的研究表明， 老年宿主与年轻宿主对PD-1 CBI的反应性受损。从机制上讲，诱人的新数据显示， 最有效地响应PD-1 CBI的CD 8 T细胞由于被激活而新近（或更少）耗尽。 最近加入了免疫系统由于初始CD 8 T细胞数量、库和功能下降， 随着年龄的增长（由于发育性程序性胸腺萎缩和既往病史的综合结果）， 我们认为，免疫老化相关的幼稚CD 8 T细胞数量和质量下降导致免疫功能下降， 耗尽较少的肿瘤反应性CD 8 T细胞库更适合于功能性拯救，从而损害了 PD-1检查点阻断疗法的疗效。这项提案的目标是了解免疫衰老是如何 幼稚CD 8 T细胞库和/或代谢功能的相关下降影响耗竭的程度， PD-1 CBI的治疗效果。我们进一步的目标是确定T细胞再生的代谢决定因素 潜力-作为调节T细胞耗竭的年龄相关的变化-并评估新的战略， 通过促进较少耗竭细胞的发育， 通过改变初始T细胞胸腺输出、激活、扩增或 细胞毒功能通过阐明影响治疗的T细胞耗竭的免疫衰老相关机制， 结果，这些研究将提供对患者反应性差异的深入了解，并将提供新的 增强治疗效果的策略。

Aging has a profound influence on immunity (Immune aging), with reports of greater susceptibility to cancers and infections, lower vaccine efficacy, and weakened immunity against persistent infections with advancing age. Nonetheless, surprisingly little is known about how cancer immunity and immunotherapy outcomes are altered with immune aging. The SEER program (Surveillance Epidemiology End Result, https://seer.cancer.gov) estimates approximately 38.4 percent of men and women will be diagnosed with cancer at some point during their lifetime. In the face of these alarming statistics, last decade has heralded remarkable new immune-based therapies with potent clinical efficacy. A frontline FDA-approved therapy - checkpoint blockade immunotherapy (CBI) using antibodies that block a dominant negative regulator of T cell responses, PD-1 or PD-L 1 - has proven to be a real tour de force in treating several refractory solid tumors (such as RCC, NSCLC, MCC and melanoma). However, not all patients respond to PD-1 CBI, the degree of responsiveness is variable, and the biomarkers predictive of therapeutic efficacy remain largely elusive. The goal of this project is to unravel the immunometabolic mechanisms underlying the widely disparate efficacy of PD-1 CBI, with "immune aging". Based on several documented immune defects with age, we predicted that therapeutic efficacy of PD-1 CBI might be compromised with advancing age. Indeed, recent studies from our laboratory and others' demonstrate impaired responsiveness to PD-1 CBI in aged versus young hosts. Mechanistically, tantalizing new data show that CD8 T cells that respond most efficiently to PD-1 CBI are newly (or less) exhausted by virtue of being recently recruited into the immune response. Since na"ive CD8 T cell numbers, repertoire and function decline with age (due to the combined result of developmentally-programmed thymic atrophy and past medical history), we propose that immune aging-related decline in na·ive CD8 T cell quantity and quality leads to a reduction in the pool of less exhausted tumor-reactive CD8 T cells more amenable to functional rescue, thus compromising the efficacy of PD-1 checkpoint blockade therapy. The goal of this proposal is to understand how immune aging related decline in na"ive CD8 T cell repertoire and/or metabolic function impacts the extent of exhaustion and therapeutic efficacy of PD-1 CBI. We further aim to define the metabolic determinants of T cell rejuvenation potential - as regulated by age-related alterations in T cell exhaustion - and evaluate novel strategies to potentially augment the therapeutic efficacy of PD-1 CBI by promoting the development of less exhausted cells that are more responsive to CBI through alterations in na·ive T cell thymic output, activation, expansion or cytotoxic function. By elucidating immune aging-related mechanisms of T cell exhaustion that influence therapy outcomes, these studies will provide insight into the disparity in patient responsiveness, and will offer novel strategies to augment therapeutic efficacy.