THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT

蒂施癌症研究所 - 癌症中心支持拨款

• 批准号: 10293872
• 负责人: Ramon E Parsons
• 金额: $ 25万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10293872
• 关键词: Academic Medical Centers; Access to Information; Administrator; Affect; Award; Bioinformatics; Biometry; Cancer Burden; Cancer Center Support Grant; Cancer Control; Cancer Patient; Cancer Research Project; Caring; Catchment Area; Clinical; Clinical Investigator; Clinical Trials; Communities; Community Networks; Development; Disease; Doctor of Philosophy; Equipment; Faculty; Family; Flow Cytometry Shared Resource; Focus Groups; Fostering; Foundations; Funding; Health Personnel; Human; Immunologic Monitoring; Incidence; Individual; Informatics; Information Technology; Infrastructure; Institutes; Leadership; Malignant Neoplasms; Microscopy; Mission; Morbidity - disease rate; Neighborhoods; New York City; Pathology; Patients; Peer Review; Pilot Projects; Prevention; Principal Investigator; Protocols documentation; Research; Research Infrastructure; Research Personnel; Scientist; Side; Site; Strategic Planning; Students; Training and Education; Translating; Translations; United States National Institutes of Health; Work; anticancer research; biobank; biomedical data science; cancer clinical trial; cancer prevention; cancer risk; cancer therapy; cancer type; clinical investigation; design; early phase trial; experience; first responder; improved; improved outcome; innovation; medical schools; meetings; mortality; mouse genetics; next generation sequencing; novel; novel therapeutics; population health; prevent; programs; public health relevance; screening; training opportunity; tumor immunology

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.

该提案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HIV患者（PWH）中非小细胞肺癌的侵略性自然病史和临床过程。肺癌现在是最常见的NADC，是PWH癌症死亡的主要原因。这种重大的疾病负担进一步加剧了恶化的肺癌结局。包括我们自己在内的几项大型研究发现，即使在治疗后，PWH的肺癌生存率也会更糟，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，这些因素导致与HIV相关的肺癌过多的风险，并且可能导致肿瘤行为。首先，我们发现长时间暴露于低CD4/CD8比率，这是一种异常免疫激活的度量，通常是在肺癌发病率之前发生的，并且与PWH中肺癌风险的明显（3倍）独立增加有关。其次，我们发现在与HIV相关肿瘤（包括肺癌）中CD8细胞的浸润增加增加，并且自相矛盾的是，这些细胞通常与结局较差有关。第三，我们发现循环T调节（TREG）细胞比例增加与PWH中的肺癌风险独立相关，PWH是该组的独特危险因素。即使在控制良好的病毒血症的情况下，与PWH中肺癌发展的独特免疫学环境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，从而在这些肿瘤中促进更大的突变负担。在这项研究中，我们将测试淋巴细胞耗尽，局部免疫抑制和促肿瘤耐受性信号传导是否会驱动肺癌的发展，这可能解释了与HIV感染相关的肺癌的过度和差的肺癌结果。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，也直接影响其行为。这些努力将产生新颖的预后策略，并提高人们对HIV对HIV+患者发病率主要来源的肺癌结果的影响。我们的具体目的是：（1）评估肿瘤微环境异常免疫激活，淋巴细胞耗尽，局部免疫抑制和耐耐受性信号对PWH中NSCLC的临床结果的影响； （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PWH和未感染的比较器中的银行活检和手术标本，并具有来自我们生物验证的表现良好的表型数据。我们将使用尖端的质量细胞仪成像技术评估库存的标本，以表征病变的浸润和周围的淋巴细胞，病变的上皮细胞和基质。然后，我们将从PWH和未感染的人对NSCLC进行序列。这项研究将提供一种创新的方法来理解对NSCLC的自然史和免疫学反应，NSCLC是PWH中发病率的主要来源。