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.

项目摘要 - 项目2 结膜鳞状细胞癌（CSCC）是病因未知的眼癌。 CSCC不成比例 影响撒哈拉以南非洲（SSA），这种环境中有晚期疾病的表现很常见。 转化为高发病率，因为晚期CSCC的治疗包括破坏性眼科手术。 视力丧失。鉴于平均年龄的平均年龄 CSCC诊断仅约40年。了解这种癌症的根本原因至关重要 制定有效的早期检测和管理策略，以避免这种公共卫生伯恩。 CSCC唯一确定的危险因素之一是HIV感染。感染艾滋病毒（PLWH）的人至少有10个 被诊断为CSCC的可能性更大。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容易受到病毒引起的癌症的影响（例如，Kaposi肉瘤，宫颈 癌症）。 PLWH中CSCC的明显升高表明感染性病因。现有研究有 原发性研究皮肤人乳头瘤病毒（HPV）类型是CSCC的潜在贡献者；然而， IARC认为皮肤HPV是癌症的非毒害。新兴数据，包括我们的初步发现， 提出了CSCC中爱泼斯坦 - 巴尔病毒（EBV）的潜在作用。我们的总体目标是确定EBV是否贡献 到PLWH中的CSCC。我们建议在来自Parirenyatwa医院的800名参与者中检验EBV假设 - 津巴布韦哈拉雷的Sekuru Kaguvi眼科单元（SKEU）。这些800名患者将被利用以完成 以下研究目的： AIM 1：比较EBV DNA检测和恶性与良性结合组织中的RNA表达 在PLWH中。该目标将检验以下假设：具有入侵CSCC的PLWH将具有1）EBV的较高患病率 检测和2）与良性眼病变的PLWH相比，EBV表达更高。 AIM 2：估计使用EBV抗体测量的改变免疫响应的患病率 面板，与无癌对照相比，与CSCC的PLWH相比。这个目标将检验PLWH的假设 具有侵入性CSCC（病例）的EBV抗体评分将比没有眼病变的PLWH（对照）更高。 目标3：估计HIV状况与CSCC临床结果之间的关联。这个目标将测试 假设PLWH和CSCC与没有HIV病例相比，CSCC诊断后的生存率较差。 探索目标。我们将以约100个CSCC病例（50例无艾滋病毒和50例）的肿瘤为免疫 根据T细胞的存在以及T细胞的评估量和空间模式，浸润或免疫被排除在外， 免疫检查点的表达和艾滋病毒状况的免疫耗尽标记。