Defining Tumor Microenvironment and Response to Immune Checkpoint Blockade in HIV-related Anogenital Squamous Cell Carcinomas (Immuno/microenvironment)

HIV 相关肛门生殖器鳞状细胞癌中肿瘤微环境的定义和对免疫检查点阻断的反应（免疫/微环境）

• 批准号: 10620043
• 负责人: HOWARD H. BAILEY
• 金额: $ 24.47万
• 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: 2022-09-16 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620043
• 关键词: AIDS related cancer; AIDS/HIV problem; Address; Administrative Supplement; Animals; Anogenital cancer; Biological Markers; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cancer Model; Cells; Cervical Squamous Cell Carcinoma; Cervix Uteri; Clinical; Collaborations; Colorectal; Complex; Data; Disease; Dysplasia; Follow-Up Studies; Formalin; Foundations; Genes; Gynecologic; HIV; HIV Seronegativity; HIV Seropositivity; Head and Neck Cancer; Health; Human; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Immune; Immune Evasion; Immune Targeting; Immunity; Immunohistochemistry; Immunologic Markers; Immunologic Surveillance; Immunologics; Immunologist; Immunotherapeutic agent; Immunotherapy; Infiltration; Institution; Keratin; Knock-out; Lead; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Malignant neoplasm of anus; Mediating; Molecular Virology; Mus; Nature; Papillomavirus; Paraffin Embedding; Pathologist; Patient Selection; Patients; Persons; Phenotype; Population; Pre-Clinical Model; Prognosis; Prognostic Marker; Publishing; Research; Research Personnel; Research Priority; Research Proposals; Risk; Role; Sampling; Squamous cell carcinoma; Stress; Surgeon; T-Lymphocyte; Testing; Tissues; United States National Institutes of Health; Vulva; Work; anti-PD-1; antiretroviral therapy; base; cancer diagnosis; cancer risk; cancer therapy; cancer type; checkpoint therapy; chemoradiation; chronic infection; design; exhaust; experience; immune checkpoint; immune checkpoint blockade; improved; individual patient; insight; macrophage; malignant oropharynx neoplasm; mortality; mouse model; multidisciplinary; neoplastic; new therapeutic target; novel; novel marker; patient response; phenotypic biomarker; pre-clinical; preclinical study; predict responsiveness; predicting response; predictive marker; ranpirnase; response; response biomarker; single-cell RNA sequencing; standard of care; tool; transcriptome; transcriptome sequencing; treatment response; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

Defining Tumor Microenvironment and Response to Immune Checkpoint Immunotherapy in HIV-related Anogenital Squamous Cell Carcinomas (Immuno/microenvironment) ABSTRACT Scientific Rationale: Human papillomavirus (HPV)-associated cancers are a growing health problem, especially amongst human immunodeficiency virus (HIV)-positive patients. Despite the decrease in mortality due to combination antiretroviral therapy, people living with HIV/AIDS (PLWH) continue to experience a high burden of anogenital HPV-related squamous cell cancers. Predictive markers for patients’ response to specific therapies are important tools for clinicians in choosing the best anti-cancer therapy for an individual patient. This includes immune checkpoint immunotherapy (ICI), which is growing in its use in patients with anogenital cancers. In a preclinical mouse model for HPV-associated neoplastic disease, we recently discovered that papillomaviruses evade host immunity to establish persistent infections that can lead to cancer by inducing expression of the host gene, Stress Keratin 17 (K17), thereby suppressing T cell mediated immune surveillance and anti-tumoral macrophages [1]. Hypothesis: Our central hypothesis is that K17 expression in anogenital squamous cell carcinoma induces an immunosuppressive tumor microenvironment (TME) with distinct features between HIV+ vs. HIV- patients, thereby defining their ICI response. Our multidisciplinary team will systematically test this hypothesis through the following two specific aims: Project Design: Aim 1: Test whether K17 is a useful marker for predicting the responsiveness of HPV+/- anogenital (cervix, vulvar, and anal) squamous cell carcinomas treated with ICI or first-line therapy in HIV+/- patients. Aim 2. Identify the TME phenotypes of HIV+ /-, HPV+/- anogenital (cervix, vulvar, and anal) cancers. Relevance: This research proposal will test a novel biomarker of response to ICI in HIV positive versus HIV negative patients with anogenital cancers and characterize the TME in HIV-associated anogenital cancers to provide mechanistic insights of the role of K17 on TME, and potentially identify novel targets for ICI. This is a collaborative P30 Administrative Supplement Application from Drs. Evie Carchman, Megan Fitzpatrick, Huy Dinh, Nathan Sherer, Paul Sondel, 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 computational biologist with experience in evaluating complex tumor immune microenvironments in several cancer types, including HPV-related cancers (Dinh), a researcher with expertise in HIV (Sherer), a senior expert in HPV infection and HPV-related cancers whose lab has developed multiple preclinical mouse models for anogenital cancer (Lambert), and a noted tumor immunologist who brings specific expertise in manipulating levels of CD4 and CD8 cells in mice, which is relevant to our proposed animal studies (Sondel).

HIV相关肿瘤微环境的定义和免疫检查点免疫治疗的反应 肛门生殖器鳞状细胞癌（免疫/微环境） 抽象的 科学依据：人乳头瘤病毒 (HPV) 相关癌症是一个日益严重的健康问题， 特别是在人类免疫缺陷病毒（HIV）阳性患者中，尽管死亡率有所下降。 由于联合抗逆转录病毒治疗，艾滋病毒/艾滋病患者 (PLWH) 的感染率持续升高 肛门生殖器 HPV 相关鳞状细胞癌的负担 患者对特定反应的预测标记。 疗法是人群为个体患者选择最佳抗癌疗法的重要工具。 这包括免疫检查点免疫疗法（ICI），该疗法在肛门生殖器疾病患者中的使用越来越多 在 HPV 相关肿瘤疾病的临床前小鼠模型中，我们最近发现： 乳头瘤病毒逃避宿主免疫力，建立持续感染，可通过诱导导致癌症 宿主基因应激角蛋白 17 (K17) 的表达，从而抑制 T 细胞介导的免疫 监测和抗肿瘤巨噬细胞[1]。 假设：我们的中心假设是 K17 在肛门生殖器鳞状细胞癌中的表达诱导 HIV+ 与 HIV- 患者之间具有独特特征的免疫抑制性肿瘤微环境 (TME)， 从而定义他们的 ICI 响应。 我们的多学科团队将通过以下两个具体目标系统地检验这一假设： 项目设计： 目标 1：测试 K17 是否是预测 HPV+/- 肛门生殖器（子宫颈、 HIV+/- 患者接受 ICI 或一线治疗的外阴和肛门鳞状细胞癌。 目标 2. 识别 HIV+/-、HPV+/- 肛门生殖器（子宫颈、外阴和肛门）癌症的 TME 表型。 相关性：该研究计划将测试 HIV 阳性与 HIV 患者对 ICI 反应的新型生物标志物 患有肛门生殖器癌症的阴性患者，并描述 HIV 相关肛门生殖器癌症的 TME 特征 提供 K17 对 TME 作用的机制见解，并有可能确定 ICI 的新靶标。 这是 Evie Carchman、Megan 博士的协作 P30 行政补充申请。 Fitzpatrick、Huy Dinh、Nathan Sherer、Paul Sondel 和 Paul Lambert 我们的多学科团队包括。 初级妇科病理学家，在 PLWH 中具有 HPV 分子病毒学和发育异常研究经验 患有艾滋病毒/艾滋病（联合项目负责人：菲茨帕特里克），一位结直肠外科医生，在治疗各种艾滋病毒/艾滋病方面具有专业知识 HPV 相关肛门生殖器疾病和使用小鼠肛门癌临床前模型的专业知识（联合项目 领导者：Carchman），一位计算生物学家，具有评估复杂肿瘤免疫系统的经验 多种癌症类型的微环境，包括 HPV 相关癌症 (Dinh)，一位具有专业知识的研究人员 HIV 博士 (Sherer)，HPV 感染和 HPV 相关癌症的资深专家，其实验室已开发出多种 肛门生殖器癌的临床前小鼠模型（兰伯特），以及一位著名的肿瘤免疫学家，他带来了特异性 操纵小鼠 CD4 和 CD8 细胞水平的专业知识，这与我们提出的动物相关 研究（桑德尔）。