Characterisation and harnessing the CD8+ Tissue Resident Memory T cell response in HPV-driven anal neoplasia.

HPV 驱动的肛门肿瘤中 CD8 组织驻留记忆 T 细胞反应的表征和利用。

基本信息

批准号：
10256111
负责人：
Anthony Kelleher
金额：
$ 14.83万
依托单位：
UNIVERSITY OF NEW SOUTH WALES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10256111
关键词：
Address Adult Affect Americas Anus Australia Biological Blood Circulation CD4 Positive T Lymphocytes CD8B1 gene CTLA4 gene Cancer Etiology Cells Cervix Uteri Characteristics Clinic Visits Clinical Trials Coupled Data Development Disease Drug Targeting Drug or chemical Tissue Distribution Dysplasia Epidemic Europe Excision Foundations Future Genital Genitalia HIV HIV Infections HPV-High Risk Head and Neck Squamous Cell Carcinoma Head and neck structure Human Papilloma Virus Vaccine Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Human papillomavirus 16 Immune Immune checkpoint inhibitor Immune response Immune system Immunity Immunologic Surveillance Incidence Inflammatory Interferon Type II Interleukin-10 Intervention Lead Learning Licensing Life Lymphocyte Lymphopenia Malignant Neoplasms Malignant neoplasm of anus Memory Microscopy Minority Molecular Morbidity - disease rate Mucous Membrane Natural History Neoplasms Operative Surgical Procedures Oropharyngeal Squamous Cell Carcinoma Pathogenesis Pathway interactions Patients Phenotype Play Population Prevention Prognosis RNA Rectum Risk Factors Role Signal Pathway Signal Transduction Squamous intraepithelial lesion T cell response T memory cell T-Lymphocyte TGFB1 gene TNF gene Time Tissues Translational Research Tumor Immunity Virus Diseases Work burden of illness clinical database co-infection combat comorbidity cytotoxic design digital fighting immune checkpoint immunoregulation improved men men who have sex with men new therapeutic target novel novel therapeutic intervention novel therapeutics premalignant prevent programmed cell death protein 1 recruit response single cell proteins sound therapeutic development tissue archive transcriptome sequencing transcriptomics treatment strategy tumor

项目摘要

Project Summary Anal cancer has a rising incidence in the Americas, Australia and parts of Europe, the major risk factor being high-risk human papilloma virus (HR-HPV). However, when a precancerous high- grade squamous intraepithelial lesion (HSIL) develops in HIV-infected hosts only a minority progresses to anal cancer in the absence of treatment, highlighting the existence of effective host immune surveillance. Our project endeavours to define the mucosal T cell mechanisms controlling HSIL progression and harness for novel therapeutic development. We leverage from the successful natural history Study of the Prevention of Anal Cancer (SPANC), that recruited HIV-infected uninfected adult men who attended 6 clinic visits over 3 years. Archived tissue sections of patients with SIL together with an existing rich clinical database represents a significant translational research opportunity. Tissue resident memory T (TRM) cells are specialised lymphocytes adapted for life in tissue, with minimal re-circulation. CD8+ TRM cells are characterised by co-expression of CD103 and CD69 and high expression of inflammatory and cytotoxic markers. There is exciting emerging data for their role in anti-tumour immunity, including in HPV-associated head and neck squamous cell carcinoma (SCC), where the proportion of tumour-infiltrating CD8+ TRM cells positively correlates with prognosis and survival. AIM 1: To quantify total and activated tissue CD8+ TRM cells in HPV16+ and HPV16- SIL and determine if HIV-co-infection has an impact on the size, distribution and phenotype of these populations. AIM 2: To define the molecular characteristics of both the T cell rich zones and stroma of patients with regressive versus persistent high grade HSIL. To determine if the presence of HIV co-infection modulates the expression of these biological pathways. AIM3: To identify novel therapeutic targets that activate CD8+ TRM cells e.g. established or emerging checkpoints PD-1, CTLA-4, LAG-3, CD39 and/or cereblon. This will be the first comprehensive study of TRM cells in anal cancer pathogenesis and the first to examine the effect of co-morbid HIV infection. We will define the role TRM cells play in HSIL regression using cutting-edge multi-plex spectral microscopy, Digital Spatial (RNA) Profiling and single-cell protein-RNASeq, providing a sound foundation for advancements of novel therapeutics development aimed at decreasing the significant burden of this disease.

项目概要肛门癌在美洲、澳大利亚和欧洲部分地区的发病率不断上升，是主要风险因素是高危人乳头状瘤病毒（HR-HPV）。然而，当癌前病变高级鳞状上皮内病变 (HSIL) 仅在少数 HIV 感染者中发生在没有治疗的情况下进展为肛门癌，强调了有效治疗的存在宿主免疫监视。我们的项目致力于定义粘膜 T 细胞机制控制 HSIL 进展并利用新疗法的开发。我们借鉴预防肛门癌的成功自然历史研究 (SPANC)，招募了感染 HIV 的未感染成年男性，这些男性参加了 6 次诊所就诊，超过 3 次年。存档的 SIL 患者组织切片以及现有的丰富临床资料数据库代表了一个重要的转化研究机会。组织驻留记忆 T (TRM) 细胞是适应组织中生活的特殊淋巴细胞，具有最小的再循环。 CD8+ TRM 细胞的特点是共表达 CD103 和 CD69 以及炎症和细胞毒性标记物的高表达。有令人兴奋的新兴数据它们在抗肿瘤免疫中的作用，包括在 HPV 相关的头颈鳞状细胞中的作用癌 (SCC)，其中肿瘤浸润 CD8+ TRM 细胞的比例呈正相关与预后和生存。目标 1：量化 HPV16+ 和 HPV16- SIL 中的总和活化组织 CD8+ TRM 细胞和确定 HIV 合并感染是否对病毒的大小、分布和表型产生影响这些人群。目标 2：定义 T 细胞富集区和基质的分子特征消退性 HSIL 患者与持续性高级别 HSIL 患者。判断是否存在 HIV 共感染的感染调节这些生物途径的表达。 AIM3：确定激活 CD8+ TRM 细胞的新治疗靶点，例如已建立或新兴的检查点 PD-1、CTLA-4、LAG-3、CD39 和/或 cereblon。这将是第一个关于TRM细胞在肛门癌发病机制中的全面研究，也是第一个检查共病艾滋病毒感染的影响。我们将定义 TRM 细胞在 HSIL 中的作用使用尖端多重光谱显微镜、数字空间 (RNA) 分析和单细胞蛋白RNASeq，为新型RNA测序技术的进步奠定了坚实的基础治疗方法的开发旨在减轻这种疾病的重大负担。