The immune system possesses checks and balances, known as immune checkpoints, to prevent it from attacking the body’s own healthy cells. These mechanisms act like brakes on immune activity. A molecule called VISTA (V-domain Ig suppressor of T cell activation) is a key checkpoint that has become a target in cancer research because tumors can exploit its function to hide from the immune system.
The Function of VISTA in the Immune System
VISTA (V-domain Ig suppressor of T-cell activation) is a protein that regulates the immune system to prevent overactivity. It is primarily found on hematopoietic cells, with high expression on myeloid cells like macrophages and dendritic cells, and also on T cells. VISTA’s main job is to maintain self-tolerance, stopping the immune system from attacking the body’s own tissues.
As a negative regulatory molecule, VISTA maintains a state of quiet readiness, or quiescence. When active, it suppresses T cell proliferation and the production of inflammatory cytokines. It achieves this by raising the activation threshold for T cells, making it harder for them to launch an attack and helping to prevent autoimmune diseases.
VISTA’s role is complex, as it can be both an inhibitory and a co-stimulatory molecule depending on the context. While its primary role is suppressive, it can interact with itself between T cells or with different binding partners. One such partner is the LRIG1 protein on T cells, which receives signals from VISTA to halt T cell replication and function.
VISTA’s Role in Cancer
While VISTA’s suppressive function is normally protective, cancer cells exploit this mechanism. Tumors create a tumor microenvironment (TME), a complex ecosystem of cancer cells, immune cells, and signaling molecules. Within this TME, VISTA expression is often elevated on myeloid cells and regulatory T cells (Tregs), creating an immunosuppressive shield around the tumor.
By activating the VISTA pathway, tumors engage the ‘brakes’ on the immune cells meant to identify and destroy them. When T cells enter the TME, the prevalent VISTA molecules can bind to their receptors, delivering a signal that shuts down their anti-tumor activity. This suppression allows cancer cells to evade immune destruction and continue to grow and spread.
The influence of VISTA is significant in cancers resistant to other immunotherapies. Some tumors may not rely on pathways like PD-1/PD-L1, instead using VISTA for immune evasion. In some cases, treatment with other checkpoint inhibitors can increase VISTA expression, suggesting it acts as a compensatory resistance pathway. This makes VISTA a target for treating cancers that do not respond to existing therapies.
Distinguishing VISTA from Other Checkpoints
VISTA has distinct characteristics compared to molecules like PD-1 and CTLA-4, especially in the types of cells where it is expressed. VISTA is predominantly found on myeloid cells within the tumor microenvironment. In contrast, PD-L1 (the binding partner for PD-1) is often expressed on tumor cells, while PD-1 and CTLA-4 are primarily found on T cells.
The timing and mechanism of action also differ. CTLA-4 is an early-acting checkpoint that regulates T cell activation during the initial priming stage. PD-1 acts later by suppressing activated T cells within the TME. VISTA influences the myeloid compartment of the TME, which shapes the T cell response and helps maintain T cells in an inactive state.
Because these pathways are not redundant, a tumor with low PD-L1 but high VISTA may not respond to PD-1 inhibitors but could be vulnerable to a VISTA-targeting drug. The independent expression patterns of these checkpoints highlight the need for distinct therapeutic strategies. Targeting VISTA provides a different angle of attack by reprogramming the myeloid cells that create the immunosuppressive environment.
Therapeutic Targeting of VISTA
VISTA’s role in immune suppression makes it a target for drug development, focusing on monoclonal antibodies. For cancer treatment, the strategy involves antagonist antibodies engineered to block VISTA’s function. By preventing VISTA from suppressing T cells within the TME, these antibodies aim to restore the immune system’s ability to attack cancer cells.
Conversely, researchers are exploring agonist antibodies for autoimmune diseases. These drugs would activate VISTA, enhancing its natural immunosuppressive function to calm the immune attack on the body’s own tissues. This dual-purpose potential highlights the context-dependent nature of the pathway.
VISTA-targeting therapies are in preclinical and clinical trials, with a focus on combination therapy. Scientists are testing VISTA inhibitors alongside existing checkpoint inhibitors, like those for PD-1 or CTLA-4, to produce a more durable anti-cancer effect. Blocking multiple immunosuppressive pathways simultaneously may overcome resistance and activate a more robust anti-tumor response.