THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT

这项建议的目的是确定免疫微环境和肿瘤遗传学的特征，这些特征推动了艾滋病毒携带者(PWH)非小细胞肺癌的侵袭性自然病史和临床病程。肺癌现在是最常见的非传染性非传染性疾病，也是威尔斯亲王医院癌症死亡的主要原因。更糟糕的肺癌结果进一步加剧了这种主要的疾病负担；包括我们自己在内的几项大型研究发现，即使考虑到治疗，PWH患者的肺癌存活率也更差，这表明癌症行为更具侵袭性。我们已经确定了几个独特的因素，这些因素导致了与艾滋病毒相关的肺癌的额外风险，也可能导致了肿瘤行为。首先，我们发现，长期暴露于低CD4/CD8比率--一种衡量免疫异常激活的指标--通常在肺癌发生之前，并与PWH患者肺癌风险显著(3倍)独立增加相关。其次，我们发现CD8细胞在HIV相关肿瘤(包括肺癌)及其周围的渗透增加，而且矛盾的是，这些细胞往往与更差的预后相关。第三，我们发现循环T调节(Treg)细胞比例的增加与PWH的肺癌风险独立相关，PWH是这一组中的一个独特的危险因素。即使在病毒血症得到很好控制的情况下，PWH中独特的免疫环境与肺癌的发生共存，也可能导致独特的肿瘤行为。此外，这些干扰可能会促进独特的肿瘤进化压力，从而在这些肿瘤中刺激更大的突变负担。在这项研究中，我们将测试淋巴细胞耗竭、局部免疫抑制和亲肿瘤耐受信号是否推动肺癌的发展，这可能解释与HIV感染相关的肺癌过度和不良结局。我们还将评估这些肿瘤的肿瘤遗传特性，这些因素也影响这些癌症的抗原性和免疫反应，但也直接影响它们的行为。这些努力将产生新的预后战略，并提高对艾滋病毒对肺癌结果的影响的理解，肺癌是艾滋病毒人发病率的主要来源。我们的具体目标是：(1)评估肿瘤微环境异常的免疫激活、淋巴细胞耗竭、局部免疫抑制和耐受信号对PWH中NSCLC临床预后的影响；(2)比较PWH和未感染患者中NSCLC驱动程序突变和突变模式的患病率。为了实现这些目标，我们将使用来自PWH的银行活组织检查和手术标本以及来自我们的生物库的具有良好特征的表型数据的未感染对照标本。我们将使用尖端的质量细胞术成像技术对保存的标本进行评估，以确定皮损浸润及其周围的淋巴细胞、皮损上皮细胞和间质的特征。然后，我们将对威斯康星医院和未感染患者的非小细胞肺癌进行测序。这项研究将为了解非小细胞肺癌的自然病史和免疫反应提供一种创新的方法，非小细胞肺癌是PWH的主要发病率来源。

The goal of this proposal is to determine features of the immune microenvironment and tumor genetics that drive the aggressive natural history and clinical course of non-small cell lung cancer in people with HIV (PWH). Lung cancer is now the most common NADC and is the leading cause of cancer deaths in PWH. This major burden of disease is further compounded by worse lung cancer outcomes; several large studies including our own have found that lung cancer survival is worse in PWH even after accounting for treatment, suggesting more aggressive cancer behavior. We have identified several unique factors that contribute to the excess risk of lung cancer associated with HIV and also may contribute to tumor behavior. First, we have found that prolonged exposure to low CD4/CD8 ratios, a measure of abnormal immune activation, often precede lung cancer incidence and are associated with a marked (3-fold) independent increase in lung cancer risk in PWH. Second, we have found increased infiltration of CD8 cells in and around HIV associated tumors (including lung cancer), and that paradoxically these cells are often associated with worse outcomes. Third, we have found that increased proportions of circulating T-regulatory (Treg) cells are independently associated with lung cancer risk in PWH, a unique risk factor in this group. The unique immunologic environment coexisting with lung cancer development in PWH even in the setting of well controlled viremia is likely to lead to unique tumor behavior. Furthermore, these disturbances are likely to promote unique tumor evolutionary pressure, thereby spurring greater mutational burden in these tumors. In this study, we will test whether lymphocyte exhaustion, local immunosuppressive and pro-tumor tolerance signaling drive lung cancer development that may explain the excess and poor outcomes of lung cancer associated with HIV infection. We will also evaluate the tumor genetic properties of these tumors, factors that also influence the antigenicity and immune response to these cancers, but also directly impact their behavior. These efforts will generate novel prognostic strategies and improve understanding of the effects of HIV on lung cancer outcomes for a major source of morbidity in HIV+ persons. Our Specific Aims are to: (1) Assess the impact of tumor microenvironment abnormal immune activation, lymphocyte exhaustion, local immunosuppression, and pro-tolerance signaling on clinical outcomes for NSCLC in PWH; (2) Compare the prevalence of NSCLC driver mutations and mutational patterns in PWH and uninfected persons. To accomplish these Aims we will utilize banked biopsy and surgical specimens from PWH and uninfected comparators with well characterized phenotypic data from our biorepository. We will evaluate the banked specimens using cutting-edge mass cytometry imaging technique to characterize the lesional infiltrating and surrounding lymphocytes, lesional epithelial cells and stroma. Then we will sequence NSCLC from PWH and uninfected persons. This study will provide an innovative approach to understanding the natural history and immunologic response to NSCLC, a major source of morbidity in PWH.