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 比率作为 HIV 相关肛门生殖器鳞状细胞的预后标志物 癌前病变和癌症 抽象的 科学依据：尽管由于联合用药，艾滋病毒感染者 (PLWH) 的死亡率有所下降 抗逆转录病毒治疗、肛门生殖器人乳头瘤病毒 (HPV) 相关的鳞状细胞异常增生和癌症 在 PLWH.1-9 中更常见 缺乏对肛门生殖器鳞状细胞癌进行风险分层的预后标志物 PLWH 中的发育异常和癌症迫切需要确定预后标志物（循环）。 血液标记物和/或上皮标记物）来预测疾病的发展和进展，特别是在 艾滋病病毒感染者。 假设：我们的中心假设是 K17 表达可能与循环低 CD4/CD8 T 相关 HIV相关前体细胞和癌症中的细胞比率反映了抑制性肿瘤微环境 肛门生殖道，因此可以预测预后。 项目设计：在目标 1 中，我们将测试我们发现的生物标志物是否因 HPV 而上调 临床前模型（角蛋白 17；K17）中的感染与进展、消退和/或预后相关 在患有肛门生殖器癌前病变和癌症的感染者中，我们将使用免疫组织化学以及。 最先进的空间单细胞多重成像来描绘肿瘤微环境和空间 艾滋病和癌症样本资源 (ACSR) 组织微阵列以及我们自己的组织之间的关系 在目标 2 中，我们将研究 HIV+ 和 HIV- 患者的肛门生殖器发育不良和癌症的微阵列。 确定循环 CD4/8 T 细胞比率和/或其他免疫细胞亚群是否可以预测临床结果 肛门生殖器癌前病变和癌症。 相关性：我们的研究将测试 PLWH 和 PLWH 中肛门生殖器疾病预后的两个潜在标志物。 更好地定义允许这些患者疾病进展的肿瘤微环境。 这是 Evie Carchman、Megan 博士的协作 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 分子病毒学和不典型增生研究经验的初级妇科病理学家 感染艾滋病毒/艾滋病的感染者（联合项目负责人：菲茨帕特里克），一位在以下方面具有专业知识的结直肠外科医生 各种HPV相关肛门生殖器疾病的治疗以及小鼠肛门癌的使用专业知识 临床前模型（联合项目负责人：Carchman），一位具有临床和临床经验的终身妇科肿瘤学家 HPV相关妇科癌症检测和治疗的研究经验（Barroilhet）， 具有评估复杂肿瘤免疫微环境记录的计算生物学家 多种癌症类型，包括 HPV 相关癌症 (Dinh)、艾滋病毒专业研究人员 (Sherer)、 以及HPV感染和HPV相关癌症方面的资深专家，其实验室已开发出多种临床前药物 肛门生殖器癌小鼠模型（兰伯特）。