THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT

该建议的目标是确定驱动HIV感染者（PWH）非小细胞肺癌侵袭性自然史和临床病程的免疫微环境和肿瘤遗传学特征。肺癌现在是最常见的非传染性癌症，也是PWH中癌症死亡的主要原因。这一重大疾病负担因肺癌预后恶化而进一步加剧；包括我们自己在内的几项大型研究发现，即使在考虑了治疗后，PWH患者的肺癌存活率也更差，这表明癌症行为更具攻击性。我们已经确定了几个独特的因素，这些因素导致与HIV相关的肺癌风险过高，也可能导致肿瘤行为。首先，我们发现长期暴露于低CD4/CD8比率（一种异常免疫激活的测量方法）通常先于肺癌发病率，并且与PWH中肺癌风险的显着（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）内部和周围的浸润增加，而矛盾的是，这些细胞往往与更糟糕的结果相关。第三，我们发现循环t调节（Treg）细胞比例的增加与PWH患者的肺癌风险独立相关，这是该人群中独特的危险因素。即使在病毒血症控制良好的情况下，PWH患者与肺癌发展共存的独特免疫环境可能导致独特的肿瘤行为。此外，这些干扰可能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、局部免疫抑制和促肿瘤耐受信号是否驱动肺癌的发展，这可能解释了与HIV感染相关的肺癌的过度和不良结局。我们还将评估这些肿瘤的肿瘤遗传特性，这些因素也会影响这些癌症的抗原性和免疫反应，但也会直接影响它们的行为。这些努力将产生新的预后策略，并提高对艾滋病毒对肺癌结局的影响的理解，这是艾滋病毒阳性人群中发病率的主要来源。我们的具体目标是：(1)评估肿瘤微环境异常免疫激活、淋巴细胞耗竭、局部免疫抑制和促耐受信号对PWH NSCLC临床结局的影响；(2)比较PWH和未感染人群中NSCLC驱动突变的患病率和突变模式。为了实现这些目标，我们将利用来自PWH和未感染比较者的活检和手术标本，并从我们的生物储存库中获得表征良好的表型数据。我们将使用先进的细胞计数成像技术来评估储存的标本，以表征病变浸润和周围的淋巴细胞，病变上皮细胞和间质。然后我们将对PWH和未感染者的NSCLC进行测序。这项研究将为了解非小细胞肺癌的自然历史和免疫反应提供一种创新的方法，非小细胞肺癌是PWH发病率的主要来源。

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.