Research Themes

Theme 1: The Virus

Over 60% of the world’s VDCs occur in Asia, and Asians appear to be uniquely susceptible to three significant infection-related cancers: Hepatitis B-related Hepatocellular Carcinoma; Helicobacter Pylori (HP)-related gastric cancer, and Epstein-Barr virus (EBV)-related Nasopharyngeal Carcinoma (NPC).

The major aims of this theme are to: 

1. Investigate the impact of virus-host interactions during tumour progression, with an emphasis on the key MHC class I pathway-CD8 Cytotoxic T cell nexus – this will include an analysis of new immune determinants (epitopes) displayed on the infected cells surface, 
2. Develop reagents such as T-cell receptor-like antibodies that facilitate the analysis of virus-infected tumours and their immune correlates during the early stages of malignant transformation, 
3. Identify the virus-induced mechanisms of tumorigenesis and immune evasion,
4. Establish the first national biobank for VDCs with connectivity to international biobanks, and
5. Study the susceptibility of EBV infection in early infancy/childhood with the concurrent screening of HLA haplotypes and TLR8 polymorphisms.

Theme 2: The Tumour

The tumour microenvironment in different VDCs, including the stroma containing cancer-associated fibroblasts (CAFs) and endothelial cells, is hypothesised to play a critical role in generating heterogeneity in response to immune checkpoint inhibitors, likely by influencing gene expression in tumour cells and the associated immune milieu.

Specific aims are to:

1. Comprehensively characterise the CD45 negative tumour cells and the non-immune components of the cancer-associated stroma (such as cancer-associated fibroblasts, or CAFs) of VDCs versus non-VDCs,
2. Determine functional differences in the immunosuppressive properties of the tumours/stroma in immunotherapy responsive (Hodgkin's disease) versus non-responsive cancers (NPC, OSCC),
3. Interrogate the temporal alterations in the genome/transcriptome pre- and post-immunotherapy treatment to study how tumour cells and their associated stroma adapt to modulate their local immune microenvironment in response to treatment with checkpoint inhibitors. 

Theme 3: Immune Microenvironment 

It is hypothesised that VDCs manipulate their immune microenvironment to induce immunosuppression that prevents effective anti-cancer immunity and curtails responses to immunotherapy.

In this theme, the specific aims are to:

1. Investigate the dynamic interface between systemic immunity and the immune microenvironment of VDCs, focusing on the immunophenotypic, molecular, and functional characterisation of tumour-infiltrating immune cells and their circulating counterparts,
2. Study the underlying conditions and cell types responsible for this immunosuppression (and curtailed responses to immunotherapy),
3. Propose and test novel combinatorial immunotherapeutics to improve the efficacy of immunotherapy in VDCs, based on discoveries made in Aims 1 and 2.

Theme 4: Metabolism

We hypothesise that VDCs display distinct changes in metabolism that generate unique metabolic microenvironments. Such changes influence and shape the phenotype of TILs to promote immunosuppression, tumour progression and/or resistance to immunotherapy.

Therefore, we aim to:

1. Characterise the metabolic footprint of the tumour microenvironment in VDCs through untargeted and targeted metabolomics and MADLI/DESI mass spectrometry imaging,
2. Investigate the tumour-associated metabolic changes that regulate immunosuppression in VDCs,
3. Interrogate the potential use of metabolic biomarkers for assessing immunotherapy response in preclinical models through in vivo metabolic imaging,
4. Identify novel metabolic targets for designing improved combination immunotherapies. 

Theme 5: Therapeutic Intervention

Theme 5 will focus on building the next generation of cutting edge antibody and cell-based immunotherapies that will leverage on the target discoveries of Themes 1-4, and rationally designing single and combination studies informed by this new knowledge, including a holistic integrated cancer immunogram for VDCs incorporating collective information from the characterisation of the VDC tumour microenvironment in Themes 1-4. A key consideration is to build therapeutic platforms and strategies that we can realistically compete in globally.

Specific aims are to:

1. Develop novel human therapeutic antibodies and versatile cellular therapy platforms with the use of gdT and antigen-specific αβ T cells,
2. Develop new adjuvant and therapeutic vaccines using neoantigen discovery and vaccine generation platforms,
3. Permeate and reduce immunosuppression in the solid tumour by the rational combination of anti-angiogenic, lymphangiogenic therapies, or vessel normalization agents with immunotherapy,
4. Discover the therapeutic and treatment biomarkers in immunotherapy clinical trial studies and preclinical models, as well as validate the efficacy through consolidating the cancer transcriptome/immunome/metabolome.