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 Genentech, 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 tumors express proteins that work as “stop signs” to prevent T cells, the immune system’s “security guards,” from recognizing and attacking them. Cancer immunotherapy may work by blocking these “stop signs” so that the immune system can do its job and destroy tumor cells.

One of these “stop signs” is a protein called PD-L1, which is expressed on multiple types of cells within tumors, including tumor cells and tumor-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. We believe antibodies against PD-L1 (anti-PDL1) may be able to disrupt this interaction, allowing T cells to remain active and attack. You can watch a video from my colleague Dr. Dan Chen here for further information on why targeting the PD-L1/PD-1 pathway is such a promising approach to cancer immunotherapy.

TIGIT: THE RED LIGHT

Discovery of the PD-L1/PD-1 “stop sign” system was a great first step, but as scientists, our work prompted us to ask a simple follow-up question: are there other “traffic signals” for T cells? Turns out, the answer is yes.

Several years ago, we discovered TIGIT (T cell immunoglobulin and ITIM domain protein), a protein expressed on T cells in many different types of cancer. 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 tumors and tumor-infiltrating immune cells called poliovirus receptor (PVR), allowing the T cell to attack the tumor. 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 tumors had different ways of “stopping” T cells. If PD-L1 was a “stop sign,” we realized that TIGIT might be a “red light.”

CLEARING THE T CELL TRAFFIC JAM

Let’s 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 the tumors we were examining, TIGIT/PVR and PD-L1/PD-1 were creating “traffic jams” for T cells. What we needed was a way to block the “stop signs” and turn the “red lights” green at the same time.

To do this, our labs created an antibody that could block TIGIT (anti-TIGIT) from binding PVR. This freed 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.

CONTINUED RESEARCH

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.

Read more about these important findings in the following papers from Genentech scientists:

Nature Immunology. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells”

Cancer Cell. “The Immunoreceptor TIGIT Regulates Antitumor and Antiviral CD8+ T Cell Effector Function”