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

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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.