Researchers are exploring new ways to harness the body’s immune system to advance cancer treatment. A key area of focus is immune checkpoints, proteins that act as brakes on immune activity. A newer molecule in this family, VISTA, has captured scientific interest.
Laboratories are developing therapeutic antibodies designed to interact with VISTA. These VISTA antibodies are an emerging immunotherapy strategy that aims to release the immune system’s brakes, allowing it to attack tumor cells more effectively. This approach seeks to broaden the reach of immunotherapy, potentially helping patients who do not respond to existing treatments.
The VISTA Immune Checkpoint
V-domain Ig suppressor of T cell activation (VISTA) is a protein that functions as an immune checkpoint regulator. Its primary role is to maintain immune system balance by suppressing T cells, a type of white blood cell that fights disease. Unlike other checkpoint proteins expressed after T cells become activated, VISTA is present on resting (naïve) T cells, keeping them in a quiet state. This function is part of the body’s natural mechanism to prevent the immune system from attacking healthy tissues.
VISTA is a member of the B7 protein family, which includes other checkpoint molecules like PD-L1, but it has a distinct structure and expression pattern. VISTA is found predominantly on myeloid cells, a category of immune cells that includes macrophages and dendritic cells, which are often abundant within tumors. It is also expressed on certain T cell populations, particularly regulatory T cells that also work to dampen immune responses. This distribution suggests VISTA plays a part in controlling immune responses from the earliest stages.
High levels of VISTA expression in some tumors have been associated with poor outcomes and resistance to other immunotherapies. By suppressing T cell function and modulating myeloid cell activity, VISTA can create an immunosuppressive shield that protects cancer cells from immune attack. This biological role makes VISTA a target for new cancer therapies designed to dismantle that shield.
How VISTA Antibodies Function
VISTA antibodies are engineered proteins that target and interfere with VISTA’s suppressive function. The primary mechanism is antagonism, where the antibody binds directly to the VISTA protein on an immune cell. This binding blocks VISTA from interacting with its partners, preventing it from sending a “stop” signal to T cells. Releasing this brake allows T cells within the tumor to become activated and mount a more effective attack against cancer cells.
Beyond blocking a signal, these antibodies can remodel the tumor microenvironment. By neutralizing VISTA on myeloid cells, the antibodies can reduce the migration of suppressive cells like myeloid-derived suppressor cells (MDSCs) into the tumor. This action shifts the local environment from immunosuppressive to pro-inflammatory and conducive to anti-tumor activity. This change can lead to an increase in the numbers and activity of both CD4+ helper and CD8+ killer T cells within the tumor.
The structural design of a VISTA antibody, particularly its Fc region, influences its therapeutic action. The Fc region is the antibody’s “tail,” and it interacts with Fc receptors on other immune cells. Depending on the antibody’s isotype, such as IgG1 or IgG4, this interaction produces different outcomes.
An IgG1 isotype often engages Fc receptors to trigger the depletion of VISTA-expressing cells through antibody-dependent cellular cytotoxicity (ADCC). In contrast, an IgG4 isotype is designed to be non-depleting, focusing on blocking the VISTA pathway without eliminating the cells. This choice depends on the therapeutic goal.
Some newer VISTA antibodies are engineered with features like pH-sensitivity. These antibodies bind strongly to VISTA only in the acidic conditions of a tumor microenvironment, with minimal binding in the neutral pH of healthy tissues. This approach concentrates the antibody’s effect at the tumor site, reducing side effects like cytokine release syndrome that can occur from widespread immune activation.
Therapeutic Development of VISTA Antibodies
The development of VISTA antibodies has progressed from laboratory models into early-stage human clinical trials. These studies are focused on evaluating the safety and potential efficacy of these new therapies in patients with advanced solid tumors. Researchers are exploring VISTA antibodies both as single-agent treatments (monotherapy) and in combination with other cancer therapies.
Several types of cancer are being targeted in these initial clinical studies based on preclinical data and VISTA expression. Non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC) are two cancers where VISTA is often highly expressed. Other cancers being explored include colorectal, ovarian, and head and neck cancers. Early trial phases are designed to determine the appropriate dosage and monitor for adverse effects.
VISTA antibodies are also being investigated in combination with other immune checkpoint inhibitors, such as those that block the PD-1/PD-L1 pathway. This is because VISTA and PD-1 regulate T cells through different, non-redundant mechanisms. Because VISTA acts on resting T cells and PD-1 acts on activated T cells, blocking both pathways simultaneously could produce a more powerful anti-tumor immune response. Overexpression of VISTA has also been linked to acquired resistance to PD-1 inhibitors, suggesting that adding a VISTA-blocking agent could help overcome this resistance.
Complexities in VISTA Research
Developing therapies that target VISTA involves several challenges rooted in its complex biology. One challenge is the uncertainty surrounding its primary binding partner, or ligand. While molecules like VSIG-3 and PSGL-1 have been identified as potential partners, the complete picture of VISTA’s interactions remains under investigation. This ambiguity makes it difficult to fully predict the biological consequences of blocking the VISTA protein.
VISTA’s function is also context-dependent. It acts as both a receptor on T cells, receiving inhibitory signals, and as a ligand on myeloid cells, sending those signals. This dual role complicates therapeutic design, as an antibody might have different effects depending on which cell type it engages. Research findings have sometimes been conflicting regarding VISTA’s precise effects, particularly in its regulation of different myeloid cell populations.
These biological intricacies have led to practical challenges in clinical development. For example, designing antibodies that achieve the desired effect without causing unwanted side effects from widespread immune activation requires careful engineering. The ongoing efforts to refine these therapies highlight the nuanced process required to translate VISTA’s biology into a safe and effective treatment.