Abstract

Over 2 million cancer cases are attributed to viruses, including EBV, HPV and HBV, and new ways to tackle these cancers would be highly beneficial. Many viruses are able to escape host immune responses by adopting a latent state, which enables them to achieve long-term infection. Each year ~210,000 cancer cases are attributed to EBV: B-cell malignancies, nasopharyngeal cancer (NPC), gastric cancer (GC), and some rare T/NK cell lymphomas, leukaemias and leiomyosarcomas. The epithelial cancers NPC and GC are the major group of EBV-associated malignancies with high mortalities, and EBV+GC is the largest category of EBV-cancer with >80,000 cases per year. Harnessing host immunity to selectively eliminate tumour virus infected cancers could benefit millions of patients. Additionally, the bacteria H.Pylori is one of the most known cancer causing pathogens of gastric cancers and the oncoprotein of CagA is a potent inducer of cell plasticity changes such as epithelial mesenchymal transition (EMT).

One of the main research focuses of my group is the molecular switches of cell plasticity – the ability of cells to change their characteristics and fate. Cell plasticity is a key feature of development, regeneration and cancer and we recently revisited the role of cancer-causing pathogens, such as H. pylori and Epstein Barr virus on their ability to control the cell plasticity of host cells and vice versa. I will discuss our recent advances in achieving an effective ‘kick and kill’ strategy to purge EBV-infected epithelial cancer cells through a combination of high throughput drug screening and state of the art single cell sequencing technologies.

Immunochemotherapy is the fourth pillar of cancer therapy but the key challenge is to understand why some patients achieve clinical benefit here whereas others do not. I will also discuss the details of a unique clinical trial of immunochemotherapy-treated inoperable oesophageal cancer, one of the cancers with the highest rising incidence in the last few decades. Our uniquely designed window-of-opportunity trial (LUD2015-005), in which 35 inoperable oesophageal adenocarcinoma patients received first-line immune checkpoint inhibitor (ICI) for four weeks (ICI-4W), followed by immunochemotherapy (ICI+CTX). Comprehensive biomarker profiling was conducted, including generation of a 65,000-cell single-cell transcriptomic atlas of esophageal cancer, as well as multi-timepoint transcriptomic profiling of EAC during ICI-4W, revealing a novel T-cell inflammation signature (INCITE) whose upregulation correlated with ICI-induced tumor shrinkage. Deconvolution of pre-treatment gastro-esophageal transcriptomes using our single-cell atlas identified high tumor monocyte content (TMC) as an unexpected ICI+CTX-specific predictor of greater overall survival (OS) in LUD2015-005 patients, and of ICI response in an independent cohort of selected gastric cancer subtypes. Tumor mutational burden was an additional independent and additive predictor of LUD2015-005 OS. TMC can improve patient selection for emerging ICI+CTX therapies in gastro-esophageal cancer.