Describing the role of VISTA, an immunoregulatory molecule involved in maintaining T-cell and myeloid quiescence, as a promising target in cancer immunotherapy.
VISTA, or V-domain immunoglobulin suppressor of T-cell activation, is an immunoregulatory molecule involved in maintaining T-cell and myeloid quiescence.1 This review describes the role of VISTA as a promising target in cancer immunotherapy.
Immune Checkpoint Molecules
Within the tumor microenvironment (TME), immune cells are often downregulated by activated inhibitory pathways. The resulting suppressed immune response can facilitate cancer progression. Research has identifi ed key immune checkpoint molecules, such as PD-1 and CTLA-4, that play a role in regulating these pathways.2 One of the recently identified inhibitory checkpoint molecules is VISTA.3 Blocking VISTA can result in immune cells proliferating in the TME, which can help prevent cancer from progressing.2
Randolph J. Noelle, PhD, professor of microbiology and immunology at the Geisel School of Medicine at Dartmouth College in Hanover, New Hampshire, provided his insights on the potential of the VISTA checkpoint molecule in an interview with Targeted Therapies in OncologyTM. Noelle and his laboratory first characterized and functionally defined VISTA over 10 years ago.1
“VISTA is a negative regulatory molecule. Blocking VISTA lowers the threshold for T-cell receptor activation of resting T cells. The frequency of T cells mounting a response to neoantigens should be increased,” Noelle said.
Other inhibitory checkpoint molecules, such as CTLA-4 and PD-1, also prevent activated T cells from achieving their effector functions. As a result, targeted therapies against CTLA-4 and PD-1 have allowed T cells to proliferate and attack cancer cells in the TME and ultimately increase survival rates of patients with cancer.4
Despite this benefit, increases in survival from therapies targeting CTLA-4 and PD-1 were only seen in a fraction of patients with cancer, but this did not extend to all cancer types. A gap remains in finding specific checkpoint targets to address most cancer types.
Many potential checkpoint targets exist in addition to VISTA, including inhibitory and stimulatory checkpoint pathways such as LAG-3, TIM-3, TIGIT, OX40, and ICOS.5 However, finding the right target is a challenge, because cancer cells of different origins and individual patients with cancer cells of similar origins may respond differently to identical targeted therapies. Immunotherapeutic intervention with VISTA is of interest to investigators.
“VISTA is an exciting new target on its own and in combination with other checkpoint inhibitors,” Noelle said. “VISTA can control the steady state activity of the resting immune system and should allow for heightened antitumor immune response.”
The Role of VISTA in Immunotherapy
Research has uncovered unique features of VISTA compared with other immune checkpoint inhibitors. Other inhibitory checkpoint regulators, such as CTLA-4 and PD-1, are expressed on T cells after T-cell activation in either the priming stage (CTLA-4, to maintain T-cell anergy) or the effector stage (PD1, to prevent T-cell exhaustion).6 However, VISTA is expressed on naïve T cells.
“A unique feature compared [with] other costimulatory molecules is that [VISTA] is constitutively expressed by the immune system,” Noelle said. VISTA is found on resting T cells and on nonactivated macrophages, Noelle added.2 Its function is to keep the immune system quiet. All other immune checkpoint inhibitors regulate the process after T cells are activated. “This gives us an opportunity to raise awareness of the resting immune system to mount immune responses to cancer,” he said.
VISTA serves as the earliest checkpoint regulator of peripheral T-cell tolerance. It is involved in enforcing quiescence in naïve T lymphocytes when exposed to self-antigens.6 Therefore, when the VISTA gene is deleted in mice, naive T cells are shown to have stronger responses to cytokine stimulation with greater expansion when exposed to antigens.
VISTA has an extracellular domain with homology to PD-L1, a B7 family ligand.1 Acting as a ligand, a VISTA-Ig fusion protein has been shown to inhibit mouse and human CD4-positive and CD8-positive T cells, as well as to reduce T-cell cytokine production such as IL-2, IL-10, TNF-α, and IFN-γ. 3 Additionally in mouse models, T cells without VISTA proliferated more than T cells with VISTA when pulsed with antigen-presenting cells.7
Furthermore, VISTA is expressed on many different cells in the TME, giving it broader potential as a target than CTLA-4 and PD-1, which are relegated to activated T cells.8 For example, VISTA is expressed on myeloid-derived suppressor cells, including microglia and neutrophils, tumor-associated macrophages, and dendritic cells that all have suppressive function in the TME.
An additional quality of VISTA exhibiting its potential in advanced cancer therapy is that its upregulation in various cancer types increases as cancer worsens by grade or stage.9 Studies have shown that VISTA gene expression was upregulated to a greater extent in higher-grade gliomas than in lower-grade gliomas, and upregulation was associated with worse patient outcomes. Similarly, VISTA has been found to be upregulated in higher grades of oral squamous cell carcinomas, gastrointestinal cancers, and prostate cancers compared with lower grades of the diseases.
VISTA may also have benefit in relation to other checkpoint inhibitors, as specific cancers do not respond well to anti–PD-1 or anti–CTLA-4 therapies but may respond to anti-VISTA approaches.
For example, pancreatic cancer does not respond well to anti–PD-1 or anti–CTLA-4 therapy. However, VISTA-Ig fusion protein inhibits the cytokine production of CD8-positive T cells in the pancreatic TME.10
Lastly, specific cancers may also develop resistance to anti–CTLA-4 or anti–PD-1 therapies. Interestingly, some cancers have been shown to upregulate VISTA in these situations. In patients with melanoma treated with anti–PD-1 therapies, VISTA was upregulated.10,11 In prostate cancer, after ipilimumab (Yervoy) therapy, VISTA inhibitory molecules increased in macrophages in the TME.
Therefore, VISTA upregulation may be a key mechanism by which cancers develop resistance to other immunotherapies.12 As a result of this finding, anti-VISTA therapies have potential for use as combination therapy with anti–CTLA-4 and anti–PD-1 therapies in a nonoverlapping fashion.
Several other cancers have been shown to have high VISTA expression with worse overall survival (OS), making VISTA a potential therapeutic target. Brcic et al found high numbers of regulatory T cells with VISTA expression in squamous cell and adenocarcinomas of the lung.13 VISTA was expressed at higher levels in microsatellite unstable colorectal cancers compared with microsatellite stable tumors.12 Xie et al showed that high VISTA expression was associated with worse OS in patients with colorectal cancer.14
Likewise, high VISTA expression has been reported in ovarian and endometrial cancers, and VISTA messenger RNA expression was positively correlated with immune escape– modulating genes.14
Furthermore, in mice with ovarian cancer, an anti-VISTA antibody prolonged the survival of tumor-bearing mice.12,15
VISTA Inhibitors in Trials
Several VISTA-targeting inhibitors are in development and have undergone phase 1 and 2 trials.
An oral agent, CA-170, targeting both VISTA and PD-L1 in a phase 2 trial showed a clinical benefi t rate of 75% and progression-free survival of 19.5 weeks in patients with nonsquamous non–small cell lung cancer (NSCLC).16
Furthermore, a phase 2 trial (NCT03201458) of patients with biliary tract cancer receiving atezolizumab (Tecentriq) with MEK inhibitor cobimetinib (Cotellic) showed that patients with higher baseline or changes in VISTA expression on circulating T cells had longer progression-free survival than those without high VISTA expression.17
Several molecules targeting VISTA are undergoing phase 1 trials. HMBD-002 is an IgG4 antibody targeting VISTA and was shown to increase infl ammatory cytokines and inhibit tumor growth in animal models.18 The therapy is in clinical trials for either monotherapy or in combination with PD-1 inhibitors for treatment of patients with triple-negative breast cancer and NSCLC.
Additionally, a phase 1 trial (NCT04475523) is ongoing to find the recommended phase 2 dose of an anti-VISTA molecule, CI-8993, in patients with relapsed or refractory solid tumors. Another agent, W0180, is an anti-VISTA antibody being explored in a phase 1 trial (NCT04564417) as monotherapy or in combination with pembrolizumab (Keytruda) to determine dosing and schedule of administration.
VISTA: Potential Challenges
Despite the potential across multiple cancer types, VISTA remains variable in expression based on the tissue, restricting the therapeutic potential of its inhibition. Although VISTA is expressed in higher levels in cholangiocarcinoma, glioblastoma multiforme, clear cell renal cell carcinoma, acute myeloid leukemia, and pancreatic adenocarcinoma, it is also expressed in low levels in many other cancer types.12 These include bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, colon adenocarcinoma, and lymphoid neoplasm diffuse large B-cell lymphoma, among others.
Furthermore, there is evidence that VISTA has complicated influences on cancer immunity. In several specific cancer types, VISTA plays stimulatory checkpoint-like roles in the activation of anticancer immunotherapy.12 In certain cancer types, increased expression of VISTA leads to prolonged OS. For instance, VISTA-positive staining in hepatocellular carcinoma and ovarian carcinoma tumor cells have shown prolonged OS compared with those with VISTA-negative expression.
In addition, VISTA expression has been significantly correlated with the density of CD8-positive tumor infi ltrating lymphocytes, indicating VISTA may be involved in increasing T-cell infiltration in the TME.12 Furthermore, in esophageal adenocarcinomas, VISTA expression was associated with a longer median OS compared with VISTA-negative patients.19 Therefore, the role of VISTA in therapy ultimately remains to be seen.12
Noelle expressed caution regarding confl icting results with VISTA. “The TME is a complicated place. [Results derived from] simply looking at gene expression without cellular or protein analysis are diffi cult to interpret,” Noelle said. “VISTA is a negative regulator and will act that way when it is highly expressed. Survival can be controlled by any number of things. It is diffi cult to associate survival with the expression of a single molecule.”
In summary, VISTA blockade can enhance antitumor immune responses. Its expression has increased in some cancer types after treatment with other immunotherapies, such as anti–PD-1/L1 and anti–CTLA-4 therapies. Therefore, VISTA may serve as a key inhibitory checkpoint molecule to target for cancer immunotherapy. Despite its promise, VISTA is not universally expressed across all cancer types. Further research to better understand the role of VISTA in relation to cancer progression across cancer types is also required. Several ongoing phase 1 and 2 trials are underway for therapies targeting VISTA across several cancer types and should help defi ne the role of such an approach. Potentially, the targeting of VISTA will lead to innovations in immunotherapy to prolong survival in patients with cancer.