TDO enzyme enables tumours to avoid detection and rejection by the immune system

Scientists from the Ludwig Institute for Cancer Research (LICR) in Brussels have identified a new target for cancer therapy, an enzyme which prevents the immune system from recognising and destroying certain types of tumours. Called tryptophan 2,3-dioxygenase or TDO, the enzyme works by depriving immune cells of tryptophan, an amino acid essential to their activity.

TDO is produced by a significant number of human tumours. Scientists also show that blocking TDO activity with a novel TDO inhibitor promotes tumour rejection in mice. The study findings were published in the Proceedings of the National Academy of Sciences (PNAS).

Cancer immunotherapy — using the body’s own immune system to attack and destroy tumours — is emerging as a promising method for cancer treatment. Clinical testing of several immunotherapeutic approaches has shown variable success. Tumours often develop survival mechanisms to prevent the attack from the immune system. Researchers are now looking to evaluate the mechanisms that enable these tumours to escape detection by the immune system.

Previously, Brussels scientists from LICR and the de Duve Institute at the Université catholique de Louvain (UCL) studied one enzyme that proved to do just that. It is known as indoleamine 2,3 dioxygenase or IDO1 for short. IDO1 is expressed in many cancers, including prostate, colon, pancreas and cervical tumours.

IDO1 blocks the immune system’s ability to reject those tumours, by depriving immune cells of tryptophan. In the PNAS study released today, the same Belgian researchers have shown that TDO is also expressed in various human tumours and degrades tryptophan in a similar manner. Tumours expressing TDO include bladder and liver cancers, as well as melanomas.

“Little is known about the TDO enzyme and its ability to trick the immune system and prevent it from destroying deadly tumours. Our research is the first to explore this relationship,” said study lead investigator, Benoit J. Van den Eynde, M.D., Ph.D., Brussels Branch Director at LICR.

The group studied a series of 104 human tumour lines of different types to confirm the activity of TDO in tumour cells. They learned that 20 tumours expressed TDO only, 17 others expressed IDO1 only and 16 expressed both. The findings suggest that TDO and IDO1 enzymes represent complementary cancer immunotherapy targets, which if blocked could potentially impact 51% of all tumours.

Using a validated mouse tumour model, researchers established that TDO expression caused tumour cells to resist immune rejection. They first vaccinated the mice with an antigen that caused them to reject the tumour. Then they injected TDO-expressing tumour cells into the immunised mice. Researchers found that immunised mice no longer rejected the TDO-expressing tumours. This demonstrated that the presence of TDO prevented the immune system from attacking tumours.

In collaboration with scientists from the University of Namur (Belgium), the team then developed an active compound to inhibit TDO enzymatic activity. “Our study showed quite beautifully that the TDO inhibitor restored the ability of mice to reject tumours despite the presence of TDO in tumour cells,” said Dr. Van den Eynde.

Research recently published in Nature (Opitz, C.A. et al.) validates today’s study results by showing that TDO expression in human glioblastomas promotes tumour progression.

The research team is moving forward to validate TDO inhibition in other preclinical models. Working closely with LICR colleagues in San Diego, the team will also conduct high-throughput screening to find a more stable TDO-inhibitor compound that can be advanced in clinical testing.

LICR plans, conducts, administers, and sponsors its own clinical trials as part of its technology development process. This process allows basic investigations to continue into early stage clinical evaluation of a new therapy, and makes the clinic an essential arm of the research enterprise.

“We will continue to search for inhibitors of TDO, an important new clinical target,” confirmed Jonathan Skipper, Ph.D., Executive Director, Technology Development at LICR. “LICR intends to license its discovery to a new commercial enterprise in the near future.”