Immune Aging in Responsiveness to Checkpoint Blockade Immunotherapies

衰老对免疫(免疫衰老)有深远的影响，有报道称更容易患上 癌症和感染，疫苗效力较低，对持续感染的免疫力减弱 年事已高。然而，令人惊讶的是，人们对癌症免疫和免疫疗法知之甚少。 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，在过去的十年里预示着以免疫为基础的新疗法具有强大的临床效力。 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细胞反应的主要负调控因子PD-1或PD-L 1-已被证明是一种真正的强效 用于治疗几种难治性实体肿瘤(如肾细胞癌、非小细胞肺癌、微囊癌和黑色素瘤)。然而，并不是所有的患者 对PD-1 CBI的反应程度是不同的，生物标志物预测治疗 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新陈代谢机制。 PD-1 CBI的疗效差异很大，其根本原因是“免疫老化”。 基于几种已有文献记载的随年龄增长的免疫缺陷，我们预测了PD-1CBI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 与年轻宿主相比，老年宿主对PD-1 CBI的反应性减弱。机械地，诱人的新数据显示 对PD-1 CBI反应最有效的CD8 T细胞最近(或更少)因 最近被招募到免疫反应中。由于天然的CD8 T细胞数量、谱系和功能下降 随着年龄的增长(由于发育程序性胸腺萎缩和既往病史的综合结果)， 我们认为，与免疫衰老相关的初始CD8 T细胞数量和质量的下降导致 耗尽较少的肿瘤反应性CD8 T细胞池更容易进行功能救援，因此 PD-1关卡阻断治疗的疗效。这项提议的目标是了解免疫衰老是如何 初级CD8 T细胞谱系和/或代谢功能的相关下降会影响衰竭的程度和 PD-1脑血流显像的疗效观察我们的进一步目标是确定T细胞恢复活力的代谢决定因素 潜力-由年龄相关的T细胞衰竭变化调节-并评估新的策略以 通过促进消耗较少的细胞的发展潜在地增强PD-1脑脊液注射的治疗效果 通过改变原始T细胞胸腺的输出、激活、扩增或 细胞毒作用。通过阐明影响治疗的T细胞耗竭的免疫老化相关机制 结果，这些研究将提供对患者反应性差异的洞察，并将提供新的 提高治疗效果的策略。

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.