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呈上升趋势，这是其主要风险 高危型人乳头瘤病毒(HR-HPV)。然而，当癌症前期的兴奋- 仅少数感染HIV的宿主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，突出了有效的存在 宿主免疫监视。我们的项目致力于确定粘膜T细胞的机制 控制HSIL进展和驾驭以开发新的治疗方法。 我们借鉴了成功的预防肛门癌的自然史研究 (Span C)，招募了感染艾滋病毒但未感染的成年男性，他们在3个月内去了6次诊所 好几年了。系统性红斑狼疮患者的存档组织切片和现有丰富的临床资料 数据库代表着一个重要的翻译研究机会。 组织驻留记忆T(TRM)细胞是一种特殊的淋巴细胞，适合在组织中生活，具有 最小限度的再循环。CD8+TRM细胞的特征是CD103和CD69共表达 炎性和细胞毒标志物的高表达。有令人振奋的新兴数据显示 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 癌(SCC)，其中肿瘤浸润性CD8+TRM细胞的比例与 与预后和存活率有关。 目的1：定量检测HPV16+和HPV16-sIL中CD8+TRM细胞总数和激活的组织CD8+TRM细胞。 确定HIV合并感染是否对HIVs的大小、分布和表型有影响 这些种群。 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 HIV共同感染的可能性调节了这些生物途径的表达。 目的：寻找能够激活CD8+TRM细胞的新的治疗靶点。 已建立或正在出现的检查点PD-1、CTLA-4、LAG-3、CD39和/或Cereblon。 这将是第一次对TRM细胞在肛门癌发病机制中的全面研究，也是第一次 以检查共病HIV感染的影响。我们将定义TRM细胞在HSIL中所扮演的角色 使用尖端多光谱显微镜、数字空间(RNA)剖析和 单细胞蛋白-RNAseq，为新技术的发展奠定了坚实的基础 治疗药物的开发旨在减轻这种疾病的重大负担。

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.