Tissue and Tumour Immunity Laboratory

Dr Ajithkumar Vasanthakumar and Prof John Mariadason

Exploiting the metabolic dependence of tumour cells for immunotherapy

The immune system plays a key role in recognising and eliminating tumours. Tumour cells however have evolved to employ multiple mechanisms to evade immune attack. Given their high energetic demand, tumour cells rapidly and efficiently use energy sources such as glucose from the tumour microenvironment (TME) making it unavailable for immune cells. Glucose catabolism by tumour cells also leads to the accumulation of intermediates such as lactic acid, which makes the TME hostile for immune cells. Tumour killing immune cells become dysfunctional in a lactic acid rich TME and fail to respond to immune checkpoint blockade therapy. Tumour cells are widely believed to rely on glycolysis for ATP production. However, glucose is the sole energy input for this metabolic pathway. Kreb’s or TCA cycle on the other hand can utilise glutamine, fatty acids and proteins as energy source to produce ATP to power the growth of tumour cells.

We propose to perturb TCA cycle to make tumours fragile and susceptible to immunotherapy. To this end, we will ablate succinate dehydrogense (SDH) enzyme in murine colon tumours using CRISPR technology. This enzyme catalyses the conversion of fumarate to succinate and ablation of SDH will lead to the accumulation of succinate within tumour cells as well as the TME. Broadly, we will investigate how the metabolite succinate directly impacts tumour growth and the influence of succinate on immune cells in the TME. Succinate is known to induce ROS and promote angiogenesis. While counterintuitive, we believe angiogenesis will facilitate recruitment of immune cells to the TME. To unequivocally understand the impact of succinate on immune cells, in particular T cells, will employ SUCNR1 (succinate receptor) deficient mouse models. Furthermore, we will combine SDH inhibition with immune checkpoint blockade to assess the therapeutic benefits of succinate on cancer immunotherapy.

This project will utilize cutting-edge molecular techniques such as CRISPR, RNAseq and ATACseq, multi-parameter flow cytometry, Immunohistochemistry and novel transgenic mouse models.

Basic training in immunology or cancer biology (Honours or Masters minimum) will be required.