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.
