CD96 is a protein found on the surface of certain immune cells. This protein is present primarily on natural killer (NK) cells and T cells, which are types of white blood cells that identify and eliminate abnormal cells in the body. It belongs to a group of proteins known as the immunoglobulin superfamily, characterized by specific structural domains.
The Role of CD96 in the Immune System
CD96 functions as a type of immune checkpoint, modulating the activity of immune cells. It serves as a regulatory mechanism, preventing the immune system from becoming overly active and potentially harming healthy tissues. This regulatory action is achieved through its interaction with another protein called CD155, also known as the poliovirus receptor (PVR).
When CD96 on an immune cell binds to CD155 on another cell, it typically sends an inhibitory signal. This signal tells the NK cell or T cell to reduce its activity, thereby maintaining immune balance and preventing uncontrolled inflammation or autoimmune responses. The precise balance of these signals helps ensure that immune responses are proportionate and targeted, protecting the body’s own cells from unintended attack.
CD96 and Cancer
The body’s immune system constantly surveys for abnormal cells, a process known as immune surveillance. However, some cancer cells have developed mechanisms to evade this detection and destruction. One such mechanism involves the CD96 pathway, which tumors can exploit to suppress immune responses. Tumor cells often express elevated levels of the CD155 protein on their surface, which is typically low or absent in normal tissues.
When an immune cell, such as an NK cell or a T cell, approaches a tumor cell, the CD96 receptor on the immune cell can bind to the abundant CD155 on the cancer cell. This interaction delivers an inhibitory signal, effectively pressing the “brake” on the immune cell’s ability to attack the tumor. By deactivating or dampening the immune response, the tumor can avoid recognition and destruction, allowing it to grow and spread unchecked.
Therapeutic Targeting of CD96
Given CD96’s role in immune evasion, researchers are exploring ways to target it in cancer treatment, a strategy known as immunotherapy. This approach often involves developing drugs, specifically monoclonal antibodies, designed to block the CD96 receptor. By physically binding to CD96, these antibodies prevent the tumor’s CD155 from engaging with and deactivating the immune cell.
This blockade effectively “releases the brakes” on the immune cells, reactivating their ability to recognize and destroy cancer cells. Such therapeutic strategies aim to restore the immune system’s natural antitumor function. Research in this area is ongoing, with preclinical studies and early-phase clinical trials investigating CD96 inhibitors for various malignancies, including melanoma, lung cancer, and colorectal cancer.
Relationship with Other Immune Receptors
CD96 does not operate in isolation but is part of a broader network of receptors that interact with CD155, influencing the overall immune response. Two other significant counterparts in this network are CD226 and TIGIT, which also bind to CD155. CD226 is an activating receptor, providing a “go” signal that promotes immune cell activity.
In contrast, TIGIT, like CD96, is another inhibitory receptor that delivers a “stop” signal to immune cells. The immune response is determined by the delicate balance of these competing signals, similar to a control panel with an accelerator (CD226) and multiple brake pedals (CD96, TIGIT). Understanding these complex interactions is informing the development of combination therapies that target multiple immune checkpoints simultaneously, potentially leading to more effective cancer treatments.