PQ3: Age-related immune deviation and cancer outcome

 描述（由申请方提供）：已在细胞亚群频率和功能以及血清细胞因子和其他因子水平方面描述了与HIV相关的免疫变化。在许多情况下，随着年龄的增长，这些变化伴随着越来越多的异质性。大多数癌症的发生率也随着年龄的增长而增加，免疫系统在控制癌症方面发挥着重要作用。因此，我们假设癌症的发病率和/或进展与年龄相关的免疫偏离有关。在这个项目中，我们将使用广泛的，高度多参数的免疫表型和功能的CyTOF测定来测试这个假设。在我们的第一个具体目标中，我们将比较未经治疗的黑色素瘤患者与匹配的健康对照，以确定在没有治疗的情况下与这种癌症相关的年龄相关免疫偏离的程度。在我们的第二个具体目标中，我们将检查入选选定免疫治疗试验的黑色素瘤和肺癌患者的免疫偏离程度。我们将比较晚期/难治性黑色素瘤患者与目标1的初治患者的免疫偏离程度。在我们的第三个具体目标中，我们将比较在肺癌和黑色素瘤的情况下，对于两种不同的免疫治疗方案，治疗响应与非响应患者的免疫偏差。我们还将确定Aim 2的预测因子在肿瘤类型和免疫治疗方案中的稳定程度。我们将研究早期治疗后样本，以确定预测标志物的稳定性，并发现可能作为反应早期预测因子的动态标志物。我们将分析来自两种肿瘤类型（黑色素瘤和肺癌）和两种免疫治疗（抗PD 1和抗PD 1+抗CD 137）的共计100例患者。我们将使用最先进的分析工具，包括SPADE和Citrus，来挖掘群体之间的差异。本研究所获得的数据将为更好地了解年龄相关免疫偏离与癌症的关系奠定基础。它还可以通过确定哪些患者通常是免疫治疗的良好候选人来改善目前可用疗法的实施，并可能允许更好地决定哪些免疫治疗对哪些患者有效。此外，该项目可以提供深入了解抗肿瘤免疫和/或肿瘤介导的免疫抑制的细胞机制。

 DESCRIPTION (provided by applicant): Age-related immune changes have been described in cell subset frequencies and functions, as well as levels of serum cytokines and other factors. In many cases, these changes are accompanied by increasing heterogeneity with age. The frequency of most cancers also increases with age, and the immune system has a prominent role in controlling cancer. We therefore hypothesize that cancer incidence and/or progression is related to age-related immune deviation. In this project, we will test this hypothesis using a broad, highly- multiparameter CyTOF assay of immune phenotype and function. In our first specific aim, we will compare therapy-naïve melanoma patients to matched healthy controls, to determine the degree of age-related immune deviation associated with this cancer in the absence of therapy. In our second specific aim, we will examine the degree of immune deviation of melanoma and lung cancer patients enrolled in selected immunotherapy trials. We will compare the degree of immune deviation of advanced/refractory melanoma patients to that of the therapy naïve patients of Aim 1. In our third specific aim, we will compare the immune deviation of therapy responsive versus non-responsive patients, in the settings of lung cancer and melanoma, for two different immunotherapy regimens. We will also determine the degree to which predictive factors from Aim 2 are stable across tumor type and across immunotherapy regimens. We will look at early post-therapy samples to determine the stability of predictive markers and to discover dynamic markers that could be early predictors of response. We will analyze a total of 100 patients from two tumor types (melanoma and lung cancer) and two immunotherapies (anti-PD1 and anti-PD1+anti-CD137). We will use state-of-the-art analytical tools, including SPADE and Citrus, to mine for differences between groups. The data obtained from this study will lay a foundation for better understanding of the relationship of age-related immune deviation and cancer. It could also improve the implementation of currently available therapies, by determining which patients are good candidates for immunotherapy generally, and possibly allow better decisions of which immunotherapies will be efficacious in which patients. Moreover, this project could provide insight into the cellular mechanisms that underlie anti-tumor immunity and/or tumor-mediated immune suppression.