Project 2: Novel investigation of Epstein-Barr virus as a potential cause of conjunctival squamous cell carcinoma among people living with HIV in Zimbabwe

项目摘要--项目2 结膜鳞状细胞癌是一种病因不明的眼癌。CSCC不成比例 影响撒哈拉以南非洲(SSA)，在那里表现为晚期疾病很常见。这 转化为高发病率负担，因为晚期CSCC的治疗包括破坏性眼科手术 致视力丧失。这可能对家庭经济生产率造成严重影响，因为平均年龄为 口腔鳞癌的诊断仅有~40年。了解这种癌症的潜在原因对于指导 制定有效的早期发现和管理战略，以避免这一公共卫生负担。 唯一已确定的慢性鳞状细胞癌危险因素之一是艾滋病毒感染。艾滋病毒携带者(PLWH)至少10岁 更有可能被诊断为CSCC。因为HIV相关的免疫抑制损害了宿主的能力 为了控制感染，PLWH容易感染病毒引起的癌症(如卡波西肉瘤、宫颈癌 癌症)。PLWH中CSCC的显著升高提示感染病因学。现有的研究已经 初步研究了皮肤人乳头瘤病毒(HPV)类型是否为CSCC的潜在贡献者；然而， IARC认为皮肤HPV不是癌症的原因。新兴数据，包括我们的初步发现， 提示Epstein-Barr病毒(EBV)在CSCC中的潜在作用。我们的总体目标是确定EBV是否有助于 到PLWH的CSCC。我们建议在来自Parirenyatwa医院的800名参与者中测试EBV假说- 津巴布韦哈拉雷的塞库鲁·卡古维眼科设备(SKEU)。这800名患者将被利用来实现 以下是研究目标： 目的1：比较良、恶性结膜组织中EB病毒DNA检测和RNA表达的差异 在PLWH。这一目标将检验这样的假设，即患有侵袭性CSCC的PLWH将有1)更高的EBV患病率 与良性眼部病变的PLWH相比，EBV的表达更高。 目标2：使用EBV抗体测量，估计免疫反应改变的流行率 在患有宫颈鳞癌的PLWH患者中，与非癌症对照组进行比较。这一目标将检验PLWH的假设 有侵袭性CSCC的病例(病例)的EBV抗体评分高于无眼部病变的PLWH(对照)。 目的3：评估HIV状态与CSCC临床结局之间的关系。这一目标将考验 假设在CSCC诊断后，与未感染HIV的患者相比，PLWH和CSCC的存活率更低。 探索性目标。我们将从大约100例CSCC病例(50例感染HIV，50例未感染HIV)中将肿瘤定性为免疫肿瘤 基于T细胞的存在而被渗透或免疫排除，并评估T细胞的数量和空间格局， 免疫检查点的表达，以及艾滋病毒状态下免疫耗竭的标志。

PROJECT SUMMARY – PROJECT 2 Conjunctival squamous cell carcinoma (cSCC) is an eye cancer with unknown etiology. cSCC disproportionately impacts Sub-Saharan Africa (SSA), a setting where presentation with advanced disease is common. This translates into a high morbidity burden, as treatment of advanced cSCC includes destructive eye surgery leading to vision loss. This can result in severe impact on household economic productivity given an average age of cSCC diagnosis of only ~40 years. It is crucial to understand the underlying cause of this cancer to guide development of effective early detection and management strategies to avoid this public health burden. One of the only identified risk factors for cSCC is HIV infection. People living with HIV (PLWH) are at least 10 times more likely to be diagnosed with cSCC. Because HIV-associated immunosuppression impairs host ability to control infections, PLWH are susceptible to cancers caused by viruses (e.g., Kaposi Sarcoma, cervical cancer). The pronounced elevation in cSCC among PLWH suggests an infectious etiology. Existing studies have primarily investigated cutaneous human papillomavirus (HPV) types as potential contributors to cSCC; however, IARC considers cutaneous HPV as non-causal for cancer. Emerging data, including our preliminary findings, suggest a potential role for Epstein-Barr virus (EBV) in cSCC. Our overall goal is to determine if EBV contributes to cSCC in PLWH. We propose to test the EBV hypothesis among 800 participants from Parirenyatwa Hospital- Sekuru Kaguvi Eye Unit (SKEU) in Harare, Zimbabwe. These 800 patients will be leveraged to accomplish the following study aims: Aim 1: Compare EBV DNA detection and RNA expression in malignant versus benign conjunctival tissue in PLWH. This aim will test the hypothesis that PLWH with invasive cSCC will have 1) higher prevalence of EBV detection and 2) higher EBV expression compared to PLWH with benign eye lesions. Aim 2: Estimate the prevalence of an altered immune response, as measured using an EBV antibody panel, in PLWH with cSCC compared to cancer-free controls. This aim will test the hypothesis that PLWH with invasive cSCC (cases) will have a higher EBV antibody score than PLWH without eye lesions (controls). Aim 3: Estimate the association between HIV status and cSCC clinical outcome. This aim will test the hypothesis that PLWH and cSCC will have poorer survival after cSCC diagnosis compared to cases without HIV. Exploratory Aim. We will characterize tumors from ~100 cSCC cases (50 with and 50 without HIV) as immune infiltrated or immune excluded based on presence of T-cells and assess quantity and spatial pattern of T-cells, immune checkpoint expression, and markers of immune exhaustion by HIV status.