School of Medical Sciences


Targeting the tryptophan metabolising enzyme, indoleamine 2,3, dioxygenase to reverse tumour-mediated immune suppression

IDO_60

The immune system in patients with advanced cancer, in the majority of cases, is markedly impaired. There is a growing body of evidence that tumours can acquire mechanisms that suppress the immune system. These mechanisms of tumour-mediated immune suppression pose a major obstacle to the success of cancer vaccines.

One mechanism whereby tumours can induce immune suppression involves increased expression of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the catabolism of the essential amino acid tryptophan. Cancer cells have been shown to express high levels of IDO, and recent reports in the literature have shown that there is increased IDO-expression by antigen-presenting cells in the draining lymph nodes of cancer patients. Silencing of the IDO gene in animal models resulted in lower rates of tumour development and growth, validating IDO as an exciting new target for cancer therapy.

We have established a new initiative at the ACSRC to investigate the potential of small molecule IDO-inhibitors as a novel approach towards restoring immune function for the treatment of cancer. We have established enzyme and cell-based assays for measuring inhibition of IDO activity. We have also established analytical methods for determining concentrations of tryptophan and its metabolites in biological fluids. Working closely with the molecular modelling group, we are probing the intermolecular interactions involved in ligand binding to the active site(s) of the IDO enzyme. This information will be used for the rational design and synthesis of novel IDO-inhibitors.

Our group is also exploring the effect of IDO expression by tumours on the host T-cell immunobiology; to better understand this mechanism of tumour-induced immune suppression.