TIGIT, which stands for T cell immunoreceptor with Ig and ITIM domains, is a protein found on the surface of certain immune cells. Scientists are actively studying TIGIT to understand its precise role in regulating immune responses. Its presence on key immune cells highlights its potential influence on how the body interacts with diseases, including cancer.
The Function of TIGIT in the Immune System
TIGIT functions as an inhibitory receptor, often referred to as an “immune checkpoint,” which acts like a dimmer switch for immune cell activity. It is present on various immune cells, including CD8+ T cells, CD4+ T cells, and regulatory T cells, as well as natural killer (NK) cells.
When TIGIT binds to its ligands on other cells, it sends a signal to the immune cell to reduce its activity. The primary ligand for TIGIT is CD155, also known as poliovirus receptor (PVR), though it can also bind to CD112. These ligands are commonly found on antigen-presenting cells, which are cells that display foreign substances to the immune system.
This interaction leads to the phosphorylation of TIGIT’s intracellular tail, specifically its ITIMs. This phosphorylation recruits phosphatases, which inactivate downstream signaling molecules within the immune cell, inhibiting its activation and proliferation. This natural mechanism helps prevent the immune system from becoming overactive, maintaining balance and protecting the body from attacking its own healthy tissues.
How Cancer Exploits the TIGIT Pathway
Cancer cells exploit this normal immune regulatory pathway to evade destruction. Many tumor cells display elevated levels of the CD155 ligand on their surface. This increased presence allows them to engage TIGIT on nearby immune cells, effectively pressing the “dimmer switch” on the anti-tumor immune response.
This continuous engagement of TIGIT by cancer cells contributes to “T-cell exhaustion.” Immune cells within the tumor environment, particularly CD8+ T cells that express high levels of TIGIT, become less effective. They lose their ability to produce important signaling molecules and eliminate cancer cells.
The TIGIT-CD155 interaction also impacts natural killer cells by directly inhibiting their ability to kill tumor cells. Furthermore, it can enhance the suppressive functions of regulatory T cells, which dampen other anti-tumor immune responses. For instance, in triple-negative breast cancer, the CD155/TIGIT axis has been shown to disrupt the glucose metabolism of CD8+ T cells, further impairing their function.
Therapeutic Strategies Targeting TIGIT
Given TIGIT’s role in immune suppression within tumors, a therapeutic approach involves developing drugs that block its activity. These drugs are typically monoclonal antibodies, known as “anti-TIGIT” antibodies. These antibodies are designed to specifically bind to TIGIT, preventing it from interacting with its ligands like CD155.
By blocking this interaction, anti-TIGIT therapies aim to release the inhibitory signals on immune cells. This action is akin to releasing the “dimmer switch” on the immune system, allowing T cells and NK cells to become more active and effective in recognizing and attacking cancer cells. The goal is to reinvigorate the patient’s own immune response against the tumor.
These anti-TIGIT therapies are currently undergoing investigation in clinical trials across various types of cancer, particularly solid tumors. Several candidates, such as Tiragolumab, Vibostolimab, and Ociperlimab, have advanced through different phases of clinical development, including late-stage trials. These studies evaluate the safety and effectiveness of TIGIT blockade as a potential new treatment option.
Combination Immunotherapies Involving TIGIT
Anti-TIGIT therapies are often studied in combination with other existing immune checkpoint inhibitors, particularly those targeting PD-1 or PD-L1. This combination strategy is based on the understanding that cancer cells often employ multiple pathways to suppress the immune system simultaneously. Blocking only one pathway may allow the cancer to use another to escape.
Combining anti-TIGIT drugs with PD-1 or PD-L1 inhibitors aims to provide a more comprehensive release of immune suppression. It is like disengaging two different braking systems that cancer cells use to slow down immune responses. This dual blockade can lead to a more potent and lasting anti-tumor effect than targeting either pathway alone.
Clinical trials, including the CITYSCAPE trial for non-small cell lung cancer, have demonstrated that combining anti-TIGIT therapies like tiragolumab with anti-PD-L1 agents like atezolizumab can result in improved objective response rates and progression-free survival. This research aims to enhance immunotherapy effectiveness.