2.3 VISTA (V-domain Ig Suppressor of T Cell Activation)
V-domain Ig. suppressor of T Cell Activation (VISTA; gene Vsir ;
also known as Dies-1, Gi24, BH-75, D1α, and PD-1H) is an emerging immune
checkpoint receptor that has garnered attention for its role in
regulating immune responses, particularly within the TME [72, 73,
74].. It is a type I transmembrane protein consisting of 279 amino
acids (AAs). It includes an extracellular IgV domain comprising 162 AAs,
a transmembrane domain spanning 21 AAs, and a cytoplasmic domain
containing 96 AAs [75]. VISTA exhibits the highest sequence homology
with PD-1 [73]. However, unlike PD-1, VISTA lacks a conventional
immunoreceptor tyrosine-based inhibition motif (ITIM) or immunoreceptor
tyrosine-based switch motif (ITSM) within its cytoplasmic domain.
Instead, the intracellular tail of VISTA contains two putative binding
sites for protein kinase C (PKC) and a proline-rich motif that likely
serves as docking sites for signaling molecules. These features suggest
that VISTA has the potential to function both as a receptor and a ligand
[73]. VISTA is predominantly expressed on myeloid cells, including
monocytes, macrophages, dendritic cells, microglia, neutrophils, and
tumoral cells as well as on certain subsets of tumor-infiltrating
lymphocytes (TILs) [72, 76]. Human VISTA has two confirmed binding
partners (ligands) with immunosuppressive functions: P-selectin
glycoprotein ligand-1 (PSGL-1), V-Set and Immunoglobulin domain
containing 3 (VSIG3) and galectin-9 . Additionally, there are less
well-confirmed ligands: VSIG8 and FOXD3 [75, 77, 78].
The main role of VISTA is to uphold an immunosuppressive environment,
which is essential for preventing excessive immune responses, thereby
maintaining the body’s homeostasis and protecting against autoimmune
tissue damage [73, 74]. However, in the context of cancer, this
immunosuppressive function can be hijacked by tumors to evade immune
detection and destruction. VISTA achieves this by delivering inhibitory
signals to T cells, dampening their activation, proliferation, and
effector functions [79]. Studies have demonstrated that
tumor-infiltrating immune cells, such as CD11b+Gr1+ myeloid cells and
FoxP3+ Tregs, can exhibit increased expression of VISTA, thereby
dampening anti-tumoral immune responses. Additionally, the hypoxic
conditions within the TME can induce overexpression of VISTA,
facilitating immune evasion by tumor cells [74, 80]
VISTA is structurally similar to other immune checkpoint molecules but
operates through distinct mechanisms [81]. It can act both as a
receptor and as a ligand, engaging in interactions that suppress T cell
activity [78]. When VISTA is expressed on antigen-presenting cells
(APCs), it interacts with counter-receptors on T cells, leading to the
inhibition of T cell activation. This interaction effectively suppresses
the immune response by preventing the T cells from mounting a robust
attack against antigens, including those presented by tumor cells [78,
79]. Conversely, when VISTA is expressed on T cells, it can receive
inhibitory signals from its ligands present on APCs. This bidirectional
inhibitory signaling further enhances immune suppression by dampening
the activation and function of T cells [78, 79].
VISTA is often significantly upregulated in tumor-infiltrating immune
cells across various cancers, including gastric cancer [82],
colorectal cancer [83], melanoma [84], prostate cancer [85],
TNBC [86], and acute myeloid leukemia [87]. However, the
significance of VISTA expression in the TME for patient survival remains
controversial, and further research is required to assess VISTA
expression and function within the TME . Recent studies on non-small
cell lung cancer(NSCLC) [88], esophageal adenocarcinoma [89],
endometrial carcinoma [90], and breast cancer [86] have
confirmed that high levels of VISTA ecpression in immune cells are
associated with a better prognosis. However, a study by Kuklinski et al.
on cutaneous melanoma found a negative correlation between VISTA
expression in immune cells and prognosis [84]. Similarly in Ovarian
Cancers, Liao et al., observed that high expression of VISTA on immune
cell was significantly associated with poor prognosis [91]. In renal
cell carcinoma (RCC), the presence of VISTA-positive immune cells in the
venous tumor thrombus, but not in the primary RCC, was associated with a
poor prognosis [92]. Additionally, recent observations have revealed
that VISTA can also be expressed on tumor cells in various cancers,
including ovarian [93], endometrial [93], gastric cancer
[94], hepatocellular carcinoma [95] and small cell lung cancer
[88].
Preclinical studies have demonstrated that blocking VISTA can
reinvigorate exhausted T cells and promote their proliferation and
cytotoxic activity against tumor cells. Blocking VISTA by anti-VISTA mAb
can also inhibit the recruitment of MDSCs and increases dendritic cells
[96]. In a study by Le Mercier et al., VISTA monoclonal antibody
(mAb) treatment enhanced the infiltration, proliferation, and effector
function of tumor-reactive T cells within the TME. VISTA blockade also
altered the suppressive nature of the TME by decreasing the presence of
monocytic myeloid-derived suppressor cells and increasing the presence
of activated dendritic cells within the TME. Additionally, VISTA
blockade impaired the suppressive function and reduced the emergence of
tumor-specific Foxp3+CD4+ Tregs [80]. In the CT26 colorectal cancer
model, treatment of small tumors with anti-VISTA alone led to a
reduction in tumor growth. When used in combination therapy for large
CT26 tumors, anti-PD-1/CTLA-4 alone was met with complete adaptive
resistance. However, the addition of anti-VISTA to the regimen resulted
in the rejection of half the tumors. They observed that single-cell RNA
sequencing (scRNA-seq) of tumor-specific CD8+ T cells demonstrated that
anti-VISTA therapy activated T-cell pathways. This was achieved by
promoting co-stimulatory genes and reducing regulators of T-cell
quiescence [74]. CA-170, a small molecule inhibitor targeting PD-L1
and VISTA, demonstrated robust restoration of T cell proliferation and
effector functions inhibited by PD-L1/L2 and VISTA. It also showed
significant anti-tumor efficacy in several immunocompetent mouse tumor
models [97]. This has led to increased interest in developing
VISTA-targeted therapies as a novel approach in cancer immunotherapy.
The first anti-VISTA antibody to undergo human testing is CI-8993.
CI-8993 is designed with putative binding sites at four residues within
the C-C’ loop of VISTA and has been demonstrated to block interactions
with both PSGL-1 and VSIG-3. It features an active IgG1 Fc domain that
enhances interactions with Fc gamma receptors and myeloid cells,
supporting antibody-dependent cell cytotoxicity (ADCC) [98]. Further
anti-VISTA antibodies BMS767) and HMBD-002 are in preclinical
development [99]. Mehta et al., used yeast surface display to
engineer an anti-VISTA antibody, SG7, which binds with high affinity to
VISTA in mice, humans, and cynomolgus monkeys. SG7, as a monotherapy and
even more effectively in combination with anti-PD1, slows tumor growth
in multiple syngeneic mouse models [99].
In particular, combining VISTA inhibitors with other immunotherapies,
such as PD-1/PD-L1/ CTLA-4 inhibitors, holds significant promise
[78]. In a murine model of colon cancer, Dr. Lines and her team
documented that anti-VISTA treatment enhanced immune cell density within
the TME, with increased post-treatment infiltration of NK cells, along
with CD45+, CD8+, and CD4+ T cells. Significant synergy was noted when
anti-PD-1 and anti-CTLA-4 treatments were combined, compared to
monotherapy. This combination resulted in further tumor growth reduction
and diminished the suppressive nature of myeloid cells within the TME
[74]. The rationale for combination therapy is that simultaneously
targeting multiple immune checkpoints can produce synergistic effects,
leading to a more robust and sustained anti-tumor immune response
[100]. For instance, while PD-1/PD-L1 inhibitors work by lifting the
”brakes” on T cells, VISTA inhibitors can further enhance T cell
activation by disrupting additional inhibitory pathways. This
multi-faceted approach can potentially overcome resistance mechanisms
that limit the effectiveness of single-agent therapies. Clinical trials
are currently underway to evaluate the safety and efficacy of VISTA
inhibitors, both as monotherapies and in combination with other
checkpoint inhibitors [101]. Several VISTA-targeting inhibitors are
being tested in phase I and II trials in patients with advanced,
metastatic or unresectable solid tumors (NCT04475523) (NCT05082610)
(NCT04564417). A phase 1 dose-escalation study (NCT04475523) is
currently being conducted in patients with advanced, treatment-resistant
solid tumors to evaluate CI-8993 (anti-VISTA antibody). So far, the
safety data suggests that the treatment is manageable, with no
dose-limiting side effects noted up to a dose of 0.6 mg/kg [102]. In
a phase II TRIAL, oral dual inhibitor targeting both VISTA and PD-L1,
known as CA-170, exhibited a clinical benefit rate of 75% and achieved
a median progression-free survival (PFS) of 19.5 weeks in a cohort of
eight previously treated non-squamous NSCLC patients [103].