THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT

该提案的目标是确定免疫微环境和肿瘤遗传学的特征，这些特征驱动HIV感染者（PWH）非小细胞肺癌的侵袭性自然史和临床过程。肺癌现在是最常见的NADC，也是威尔斯亲王医院癌症死亡的主要原因。这种主要的疾病负担进一步加剧了更糟糕的肺癌结果;包括我们自己在内的几项大型研究发现，即使在考虑治疗后，PWH的肺癌生存率也更差，这表明癌症行为更具侵略性。我们已经确定了几个独特的因素，有助于与艾滋病毒相关的肺癌的过度风险，也可能有助于肿瘤的行为。首先，我们发现长期暴露于低CD 4/CD 8比值（一种异常免疫激活的指标）通常先于肺癌发病，并与PWH中肺癌风险的显著（3倍）独立增加相关。其次，我们发现HIV相关肿瘤（包括肺癌）中和周围的CD 8细胞浸润增加，而且这些细胞通常与更差的结果相关。第三，我们发现循环调节性T细胞（Treg）比例的增加与PWH中的肺癌风险独立相关，这是该组中的一个独特风险因素。PWH中与肺癌发展共存的独特免疫环境，即使在病毒血症得到良好控制的情况下，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，从而刺激这些肿瘤中更大的突变负担。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传导是否驱动肺癌的发展，这可能解释与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，这些因素也会影响对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预后的影响的理解，这是艾滋病毒阳性人群发病率的主要来源。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传导对PWH中NSCLC临床结局的影响;（2）比较PWH和未感染者中NSCLC驱动突变和突变模式的患病率。为了实现这些目标，我们将利用来自PWH的库存活检和手术标本以及来自我们生物储存库的未感染对照品的良好表征的表型数据。我们将使用尖端的质谱细胞成像技术对库存标本进行评估，以表征病变浸润和周围淋巴细胞、病变上皮细胞和间质。然后我们将测序PWH和未感染者的NSCLC。这项研究将提供一个创新的方法来了解自然史和免疫反应的非小细胞肺癌，在PWH的发病率的主要来源。

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.