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).

定义肿瘤微环境和免疫检查点免疫治疗在hiv相关的反应