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 2：对 Epstein-Barr 病毒作为津巴布韦艾滋病毒感染者结膜鳞状细胞癌潜在原因的新调查

• 批准号: 10598376
• 负责人: Margaret Ziona Borok
• 金额: $ 16.41万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-03 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598376
• 关键词: AIDS related cancer; Africa South of the Sahara; Age; Antibodies; Benign; Biological Markers; Blindness; Blood; CD3 Antigens; CD8B1 gene; CTLA4 gene; Cancer Etiology; Carcinoma; Cells; Clinic; Clinical; Conjunctival Squamous Cell Carcinoma; Cutaneous; DNA analysis; Data; Detection; Development; Diagnosis; Early Diagnosis; Economics; Enrollment; Epstein-Barr Virus Infections; Epstein-Barr Virus-Related Malignant Neoplasm; Etiology; Evaluation; Exclusion; Eye; FOXP3 gene; Frequencies; Future; Genetic Transcription; Goals; Grouping; HIV; HIV Infections; High Prevalence; Hospitals; Household; Human Herpesvirus 4; Human Papillomavirus; Immune; Immune response; Immunologic Markers; Immunosuppression; Impairment; Incidence; Individual; Infection Control; International Agency for Research on Cancer; Investigation; Kaposi Sarcoma; Laboratories; Lesion; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Measures; Morbidity - disease rate; Oncology; Ophthalmologic Surgical Procedures; Outcome; Participant; Patients; Pattern; Persons; Population; Predisposition; Prevalence; Preventive; Productivity; Public Health; Reporting; Research; Risk; Risk Factors; Role; Specimen; T-Lymphocyte; Testing; Time; Tissues; Translating; Tumor Tissue; Tumor-infiltrating immune cells; Viral; Viral Proteins; Virus; Virus Diseases; Vital Status; Zimbabwe; advanced disease; biobank; biological sex; biological specimen archives; cancer risk; comparison control; early detection biomarkers; exhaustion; immune cell infiltrate; immune checkpoint; malignant neoplasm of eye; mortality; novel; programmed cell death ligand 1; programmed cell death protein 1; sex; targeted treatment; tumor; viral DNA; viral detection; virus related cancer

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.

项目概要-项目2 结膜鳞状细胞癌（cSCC）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，晚期疾病的表现是常见的。这 转化为高发病率负担，因为晚期cSCC的治疗包括破坏性眼部手术， 视力丧失这可能对家庭经济生产力造成严重影响，因为平均年龄为 CSCC诊断仅约40年。关键是要了解这种癌症的根本原因， 制定有效的早期发现和管理战略，以避免这种公共卫生负担。 CSCC唯一确定的风险因素之一是HIV感染。艾滋病毒感染者（PLWH）至少10岁 更有可能被诊断为cSCC。因为HIV相关的免疫抑制会损害宿主的能力 为了控制感染，PLWH易患病毒引起的癌症（例如，颈部卡波西肉瘤 癌症）。PLWH中cSCC的显著升高提示感染性病因。现有的研究 主要研究了皮肤人乳头瘤病毒（HPV）类型作为cSCC的潜在贡献者;然而， IARC认为皮肤HPV与癌症无关。新的数据，包括我们的初步发现， 提示Epstein-Barr病毒（EBV）在cSCC中潜在作用。我们的总体目标是确定EB病毒是否有贡献 到PLWH的cSCC。我们建议在Parirenyatwa医院的800名参与者中测试EBV假设- 津巴布韦哈拉雷的Sekuru Kaguvi眼科中心。这800名患者将被用来完成 研究目的如下： 目的1：比较恶性与良性结膜组织中EB病毒DNA检测和RNA表达的差异 在PLWH。这一目的将检验以下假设，即伴侵袭性cSCC的PLWH将具有1）更高的EBV患病率 检测和2）与具有良性眼部病变的PLWH相比更高的EBV表达。 目的2：使用EBV抗体测量，估计免疫应答改变的患病率 图中，PLWH伴cSCC与无癌症对照相比。这一目标将检验PLWH 具有侵袭性cSCC的患者（病例）将具有比没有眼部病变的PLWH（对照）更高的EBV抗体评分。 目的3：评估HIV状态与cSCC临床结局之间的相关性。这一目标将考验 假设PLWH和cSCC在cSCC诊断后的生存率低于无HIV的病例。 探索目标。我们将对来自约100例cSCC病例（50例有HIV，50例无HIV）的肿瘤进行免疫学特征分析， 基于T细胞的存在和评估T细胞的数量和空间模式， 免疫检查点表达和通过HIV状态的免疫耗竭标志物。