Clearing traffic jams in tumours
Cancer immunotherapy is one of the most exciting areas of research today. It marks a new area of research in our fight against cancer, and some think it could become the ‘fourth pillar’ in the history of potential treatment options, alongside surgery, chemotherapy and radiation.
Part of this excitement stems from the fact that there is more than one way to harness the power of our immune systems; we may be able to achieve similar results using different biological tools. Our immune systems are complex, and a protein called TIGIT, discovered at Roche, may be yet another way to activate the immune system against cancer.
PD-L1: the Stop sign
Cancer is smart, and it has become exceptionally good at hiding from our immune systems. Some types of tumours express proteins that work as ‘stop signs’ to prevent T cells, the immune system’s ‘security guards,’ from recognising and attacking them. Cancer immunotherapy may work by blocking these ‘stop signs’ so that the immune system can do its job and destroy tumour cells.
One of these ‘stop signs’ is a protein called PD-L1, which is expressed on multiple types of cells within tumours, including tumour cells and tumour-infiltrating immune cells. When PD-L1 binds to its partner protein PD-1 on the surface of T cells, it effectively shuts down the T cell. Antibodies against PD-L1 may be able to disrupt this interaction, allowing T cells to remain active and attack.
TIGIT: the red light
Discovery of the PD-L1/PD-1 ‘stop sign’ system was a great first step, but are there other ‘traffic signals’ for T cells? As it turns out, the answer is yes.
Several years ago, TIGIT (T cell immunoglobulin and ITIM domain protein), a protein expressed on T cells in many different types of cancer, was discovered. What’s particularly interesting about TIGIT is that it seems to stop T cells from attacking in a different way than the PD-L1/PD-1 pathway.
TIGIT is normally found on T cells alongside another protein called CD226. When working properly, CD226 can bind to a protein on tumours and tumour-infiltrating immune cells called poliovirus receptor (PVR), allowing the T cell to attack the tumour. Let’s call this the ‘green light’ for T cells.
TIGIT, however, can inhibit CD226 and preferentially bind to PVR instead. By pushing CD226 out of the way, TIGIT can prevent T cells from attacking cancer cells.
This suggested that cells within tumours had different ways of ‘stopping’ T cells. If PD-L1 was a ‘stop sign,’ then TIGIT might be a ‘red light.’
Clearing the T cell traffic jam
Imagine T cells as cars on a street in the middle of a traffic jam. At each intersection they encounter either stop signs or stop lights. This occurs block after block, and the cars are at a standstill. In a similar way, TIGIT/PVR and PD-L1/PD-1 create ‘traffic jams’ for T cells within tumours. What was needed was a way to block the ‘stop signs’ and turn the ‘red lights’ green at the same time.
To do this, an antibody was created that could block TIGIT (anti-TIGIT) from binding PVR. This frees up CD226 to bind PVR instead and turn the stop light ‘green.’ Blocking the ‘stop signs’ and turning the ‘red lights’ green may potentially clear the traffic and allowing T cells to destroy cancer cells.
Taking advantage of multiple ways to harness the power of our immune systems could be the future of cancer immunotherapy. We continue to study the role of TIGIT and other molecules in their ability to activate immune cells, and by following the science, hope to discover even more ways to prevent cancer from creating traffic jams.