Stress keratin 17 and CD4/8 ratio as prognostic markers in HIV-related anogenital squamous cell precancers and cancers (Biospecimens/Biocohort)

应激角蛋白 17 和 CD4/8 比率作为 HIV 相关肛门生殖器鳞状细胞癌前病变和癌症的预后标志物 (Biospecimens/Biocohort)

• 批准号: 10620051
• 负责人: HOWARD H. BAILEY
• 金额: $ 23.9万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620051
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Administrative Supplement; Aggressive Clinical Course; Anogenital cancer; Anus; Basic Science; Bioinformatics; Biological Markers; Biopsy; Blood; CD4 Positive T Lymphocytes; CD4/CD8 ratio procedure; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Center; Carcinoma; Cell Count; Cells; Clinical; Clinical Research; Colorectal; Complex; Data; Detection; Development; Disease; Disease Progression; Dysplasia; Epithelial; Flow Cytometry; Gynecologic; Gynecologic Oncologist; HIV; HIV risk; Head and Neck Squamous Cell Carcinoma; Human; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Immune; Immune Evasion; Immunohistochemistry; Immunologics; Immunotherapy; Incidence; Keratin; Lesion; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of anus; Mediating; Modality; Molecular Virology; Mus; Oncology; Outcome; Pathologist; Pathology; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Predisposition; Prognosis; Prognostic Marker; Research Personnel; Resistance; Risk; Squamous Cell; Stress; Surgeon; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissue Microarray; Translating; Universities; Viral Load result; Wisconsin; antiretroviral therapy; cancer specimen resource; cancer therapy; cancer type; clinical care; cohort; design; disorder risk; experience; high dimensionality; high risk; immune function; improved; mortality; mouse model; multidisciplinary; multiplexed imaging; neoplastic; patient stratification; pre-clinical; predict clinical outcome; premalignant; prognosis biomarker; prognostic; prognostic value; ranpirnase; response; risk stratification; screening; spatial relationship; standard of care; treatment response; tumor; tumor immunology; tumor microenvironment; tumor progression; tumor-immune system interactions

Stress keratin 17 and CD4/8 ratio as prognostic markers in HIV-related anogenital squamous cell precancers and cancers ABSTRACT Scientific Rationale: Despite the decrease in mortality people living with HIV (PLWH) due to combination antiretroviral therapy, anogenital human papillomavirus (HPV)-related squamous dysplasia and cancer are more common among PLWH.1–9 There is a lack of prognostic markers to risk stratify anogenital squamous dysplasia and cancer among PLWH. There is a critical need to identify prognostic markers (circulating blood markers and/or epithelial markers) to predict disease development and progression particularly in PLWH. Hypothesis: Our central hypothesis is that K17 expression may correlate with circulating low CD4/CD8 T cell ratio, reflective of a suppressive tumor microenvironment, in HIV-associated precancers and cancers of the anogenital tract, and, therefore, predict prognosis. Project Design: In Aim 1, we will test whether a biomarker we found upregulated in response to HPV infection in preclinical models (keratin 17; K17) correlates with progression, regression and/or prognosis among PLWH with anogenital precancers and cancers. We will use immunohistochemistry as well as cutting edge spatial single cell multiplex imaging to profile the tumor microenvironment and spatial relationships in AIDS and Cancer Specimen Resource (ACSR) tissue microarrays, and our own tissue microarrays among anogenital dysplasia and cancers from HIV+ and HIV- patients. In Aim 2, we will determine if circulating CD4/8 T cell ratio and/or other immune cell subsets predict clinical outcomes in anogenital precancers and cancers. Relevance: Our study will test two potential markers of prognosis of anogenital disease among PLWH and better define the tumor microenvironment that allows for disease progression in these patients. This is a collaborative P30 Administrative Supplement Application from Drs. Evie Carchman, Megan Fitzpatrick, Huy Dinh, Nathan Sherer, Lisa Barroilhet, and Paul Lambert. Our multidisciplinary team includes a junior gynecologic pathologist with experience in HPV molecular virology and dysplasia studies among PLWH with HIV/AIDS (Co-Project leader: Fitzpatrick), a colorectal surgeon with expertise in the treatment of various HPV-associated anogenital diseases and expertise in use of mouse anal cancer preclinical models (Co-Project leader: Carchman), a tenured gynecologic oncologist with clinical and research experience in detection and treatment of HPV-related gynecologic cancers (Barroilhet), a computational biologists with track record in evaluating complex tumor immune microenvironments in multiple cancer types, including HPV-related cancers (Dinh), a researcher with expertise in HIV (Sherer), and a senior expert in HPV infection and HPV-related cancers whose lab has developed multiple preclinical mouse models for anogenital cancer (Lambert).

应激角蛋白17和CD4/8比值可作为HIV相关肛门生殖器鳞状细胞的预后标志 癌前病变与癌症 摘要 科学依据：尽管艾滋病毒携带者(PLWH)的死亡率因联合治疗而下降 抗逆转录病毒治疗后，肛门生殖器人类乳头瘤病毒(HPV)相关的鳞状上皮不典型增生和癌症 更常见的是在PLWH1-9中，缺乏预后标记物来分层肛门生殖鳞状细胞 PLWH中有不典型增生和癌。迫切需要确定预后标志物(循环 血液标志物和/或上皮标志物)来预测疾病的发展和进展，特别是在 PLWH。 假设：我们的中心假设是K17的表达可能与循环中低CD4/CD8 T有关 细胞比率，反映抑制性肿瘤微环境，在HIV相关的癌前病变和 肛门生殖道，因此，预测预后。 项目设计：在目标1中，我们将测试我们发现的生物标记物是否因HPV而上调 临床前模型(角蛋白17；K17)中的感染与进展、退化和/或预后相关 在患有肛门生殖前期癌和癌症的PLWH中。我们将使用免疫组织化学以及 尖端空间单细胞复合成像研究肿瘤微环境和空间分布 艾滋病与癌症标本资源(ACSR)组织芯片和我们自身组织的关系 HIV+和HIV-患者的肛门发育不良和癌症之间的微阵列。在目标2中，我们将 确定循环中的CD4/8T细胞比率和/或其他免疫细胞亚群是否可以预测临床结果 肛门生殖前期癌症和癌症。 相关性：我们的研究将在PLWH和PLWH之间测试两个潜在的肛门生殖疾病预后标志物 更好地定义允许这些患者疾病进展的肿瘤微环境。 这是Megan的Evie Carchman博士合作的P30行政补充申请 Fitzpatrick，Huy Dinh，Nathan Sherer，Lisa Barroilhet和Paul Lambert。我们的多学科团队 包括一名具有HPV分子病毒学和异型增生研究经验的初级妇科病理学家 在患有艾滋病毒/艾滋病的PLWH(联合项目负责人：Fitzpatrick)中，一位在以下方面具有专长的结直肠外科医生 各种HPV相关性肛门生殖疾病的治疗和小鼠肛门癌的专业知识 临床前模型(联合项目负责人：Carchman)，终身妇科肿瘤学家，临床和 人乳头瘤病毒相关性妇科癌症(Barroilhet)的检测和治疗研究体会 计算生物学家在评估复杂的肿瘤免疫微环境方面有良好的记录 多种癌症类型，包括HPV相关癌症(Dinh)，具有艾滋病毒专业知识的研究人员(Sherer)， 以及HPV感染和HPV相关癌症的高级专家，其实验室已发展出多个临床前 小鼠肛门癌模型(Lambert)。