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

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，突出了有效的 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。

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.