WEHI PhD Completion Seminar hosted by Professor Marie-Liesse Labat

Eddy Yao
PhD Student – Labat Laboratory, Personalised Oncology division, WEHI

Targeting tumour-specific regulatory T-cells to improve response to immune checkpoint blockade in lung adenocarcinoma

L7W Seminar Room

Join via TEAMS

Including Q&A session      

Lung cancer remains the leading cause of cancer deaths worldwide, accounting for at least 1.8 million deaths globally. Despite the advent of immunotherapies and our increased understanding of the mechanisms underlying tumour immune evasion, the 5-year survival rate for lung cancer patients remains dismally low at 22%.

Over the past decade, there has been growing interest in how immunosuppressive regulatory T-cells (Tregs) limit anti-tumour immune responses in cancer. Tregs are enriched in many solid tumours, including non-small cell lung cancer, and their abundance has been correlated with immunotherapy resistance and poor survival. Emerging evidence suggests that tumour-infiltrating Tregs (TI-Tregs) adopt a unique transcriptomic signature compared to other Treg subsets and may present a vulnerability that could be exploited to enhance anti-tumour immunity.

In this talk, I will focus on how we uncovered a unique signature of TI-Tregs in the KrasG12Dp53fl/fl mouse model of lung adenocarcinoma (LUAD), the most common subtype of lung cancer, and how we subsequently explored the functional relevance of selected TI-Treg-specific genes using repurposed inhibitors and preliminary CRISPR knockout studies. We first explored whether BH3 mimetics could be repurposed to selectively deplete activated TI-Tregs in LUAD and enhance anti-tumour immunity. In parallel, we utilised CITE-seq (cellular indexing of transcriptomes and epitopes) single-cell profiling to uncover potential novel candidate genes selectively expressed in TI-Tregs. Finally, we functionally validated our top tumour-specific candidate in vitro and in vivo by evaluating the impact of its inhibition on Treg function and anti-tumour immunity. Collectively, this work builds the foundation for future functional studies aimed at targeting TI-Tregs to enhance anti-tumour immunity in LUAD.

All welcome!