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).

定义HIV相关的肿瘤微环境和对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） 摘要 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， 尤其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/艾滋病感染者（PLWH）继续经历高风险， 肛门生殖器HPV相关鳞状细胞癌的负担。患者对特异性抗体应答的预测标志物 治疗是临床医生为个体患者选择最佳抗癌治疗的重要工具。 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。 癌的在HPV相关肿瘤疾病的临床前小鼠模型中，我们最近发现， 乳头状瘤病毒逃避宿主免疫，建立持续感染，通过诱导 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 监视和抗肿瘤巨噬细胞[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了一种新的肿瘤发生机制。 免疫抑制性肿瘤微环境（TME）在HIV+与HIV-患者之间具有不同特征， 从而定义它们的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测试这一假设： 项目设计： 目的1：测试K17是否是预测HPV+/-肛门生殖器（宫颈， 外阴和肛门）鳞状细胞癌在HIV+/-患者中接受ICI或一线治疗。 目标2.确定HIV+ /-、HPV+/-肛门生殖器（宫颈、外阴和肛门）癌的TME表型。 相关性：这项研究计划将测试一种新的生物标志物，用于HIV阳性与HIV阳性患者对ICI的反应。 阴性肛门生殖器癌患者，并描述HIV相关肛门生殖器癌的TME， 提供K17对TME作用的机制见解，并可能识别ICI的新靶点。 这是一个合作的P30行政补充申请从博士. Evie Carchman，梅根 菲茨帕特里克、胡伊丁、内森谢勒、保罗桑德尔和保罗兰伯特。我们的多学科团队包括 具有在PLWH中进行HPV分子病毒学和发育不良研究经验的初级妇科病理学家 艾滋病毒/艾滋病（共同项目负责人：菲茨帕特里克），一个结直肠外科医生与治疗各种专业知识， HPV相关的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（合作项目 领导人：Carchman），一位在评估复杂肿瘤免疫方面有经验的计算生物学家 微环境中的几种癌症类型，包括HPV相关的癌症（Dinh），研究人员与专业知识 在艾滋病毒（Sherer），在HPV感染和HPV相关癌症的高级专家，其实验室已经开发了多个 肛门生殖器癌的临床前小鼠模型（Lambert），以及一位著名的肿瘤免疫学家，他带来了特异性的 在小鼠中操纵CD 4和CD 8细胞水平的专业知识，这与我们提出的动物相关 研究（Sondel）。