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。

• 批准号: 10435548
• 负责人: Anthony Kelleher
• 金额: $ 12.13万
• 依托单位: UNIVERSITY OF NEW SOUTH WALES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10435548
• 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; Persons; 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

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.

项目摘要 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， 高危型人乳头瘤病毒（HR-HPV）。然而，当癌前高- 只有少数HIV感染者会发生鳞状上皮内病变（HSIL 在没有治疗的情况下进展为肛门癌，凸显了有效治疗的存在 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的进展和开发新的治疗方法。 我们利用成功的自然史研究预防肛门癌 （SPANC），招募了感染艾滋病毒的未感染成年男子，他们在3年内参加了6次诊所就诊， 年SIL患者的存档组织切片以及现有丰富的临床 数据库是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化淋巴细胞， 最小的再循环CD 8 + TRM细胞的特征在于共表达CD 103和CD 69 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相关的头颈部鳞状细胞中的作用 肿瘤浸润性CD 8 + TRM细胞的比例正相关 预后和存活率。 目的1：定量HPV 16+和HPV 16- SIL中总的和活化的组织CD 8 + TRM细胞， 确定艾滋病毒合并感染是否对病毒的大小、分布和表型产生影响， 这些人口。 目的2：明确T细胞富集区和间质的分子特征。 退行性与持续性高级别HSIL患者。以确定是否存在 艾滋病毒合并感染调节这些生物途径的表达。 目的3：鉴定激活CD 8 + TRM细胞的新的治疗靶点，例如 已建立或出现的检查点PD-1、CTLA-4、LAG-3、CD 39和/或cereblon。 这将是第一个全面研究TRM细胞在肛门癌发病机制和第一个 来检测艾滋病病毒感染的影响。我们将定义TRM细胞在HSIL中的作用 使用先进的多重光谱显微镜、数字空间（RNA）分析和 单细胞蛋白-RNASeq，为新的 旨在减少这种疾病的显著负担的治疗方法的发展。