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Page 8 of 14 Rabadi et al. J Cancer Metastasis Treat 2022;8:24 https://dx.doi.org/10.20517/2394-4722.2022.06

Table 1. Predicted outcomes of VISTA blockade with PD-1 or CTLA-4 blockade
Co- Immune checkpoint expression in the TME and relevant data Proposed impact on the TME
blockade
[64]
VISTA + VISTA on MDSCs associates with PD-1 on T cells in AML Co-blockade of VISTA and PD-1 reduces the
PD-1 VISTA expression ↑ on intratumoral lymphocytes in metastatic melanoma after likelihood of developing resistance by blocking
[10]
anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combination therapy VISTA-related compensatory immune escape
[46]
VISTA expression associates with PD-1 and PD-L1 in NSCLC , pathways in myeloid and T cells
craniopharyngioma [75] , and ENKTCL [76]
+
VISTA + High VISTA expression on TAMs and CD68 macrophages in pancreatic cancer Co-blockade of VISTA and CTLA-4 may reduce
CTLA-4 and PDAC, respectively [40,55] adaptive resistance to anti-CTLA-4,
In OSC, VISTA is overexpressed in tumor-infiltrating ICs and associated with and have complementary impacts on T cell
PD-L1 and CTLA-4 expression [39] activation because VISTA
VISTA expression ↑ in tumor tissue, blood monocytes, and tumor-associated regulates T cells prior to activation and CTLA-4
+ + [11]
CD4 and CD8 T cells in PC after anti-CTLA-4 treatment regulates T cells after activation
VISTA: V-domain Ig Suppressor of T cell Activation; TME: tumor microenvironment; MDSCs: myeloid-derived suppressor cells; AML: acute
myeloid leukemia; CT: combination therapy; ENKTCL: extranodal Natural killer/T-cell lymphoma; GC: gastric cancer; GIST: gastrointestinal
stromal tumor; CRC: colorectal cancer; ICs: immune cells; NSCLC: non-small cell lung cancer; OSC: oral squamous carcinoma; OSCC:
oropharyngeal squamous cell carcinoma; PBMC: peripheral blood mononuclear cells; PC: prostate cancer; PDAC: pancreatic ductal
adenocarcinoma; RCC: renal cell carcinoma. TAMs: tumor associated macrophages.

VISTA . While these proteins may bind VISTA under certain conditions, the biological relevance of these
[75]
interactions as counter-receptors for VISTA is not yet clear, as VSIG-3 and VISG-8 are minimally expressed
in secondary lymphoid organs where VISTA interactions are expected to occur . In multiple tumor
[83]
models (B16F10, MC38, and 4T1), SG7, an antibody that prevents both PSGL-1 and VSIG-3 from binding
to VISTA, slowed tumor growth . Unlike other VISTA antibodies that have demonstrated an Fc
[84]
[84]
crosslinking requirement, this clone is Fc-silent . Combination therapy of SG7 and anti-PD-1 resulted in a
synergistic effect in the MC38 model, slowing tumor growth more than either antibody alone .
[84]
Most recently described is the interaction between VISTA and syndecan-2, a monocyte proteoglycan .
[76]
This interaction was identified via CRISPR/Cas9 screenings and demonstrated that heparan sulfate
proteoglycan (HSPG) pathway enzymes and syndecan-2 mediate VISTA binding to monocytes . The
[76]
HSPG pathway is important in monocyte chemotaxis, migration, and maturation . The syndecan-2
[85]
antibody prevented the VISTA antibody from binding primary human monocytes, and like the VISTA
monoclonal antibodies in clinical trials, this antibody demonstrated the requirement for Fc crosslinking.
Interestingly, syndecan-2 is upregulated in some of the same cancers as VISTA, such as colorectal and
prostate, as previously discussed [86,87] . This indicates that VISTA antagonism could have an activating effect
on monocytes by blocking the interaction between VISTA and syndecan-2 in the TME.

Lastly, VISTA has also been reported to interact with itself via homophilic cis and trans interactions. This
occurs in the context of p53-induced VISTA expression, which can lead to signaling-mediated phagocytic
clearance of apoptotic cells . However, another group was unable to verify this homotypic interaction of
[77]
VISTA with itself , so this interaction may only occur under particular conditions. Identifying the binding
[74]
partner(s) of VISTA is challenging due to the lack of functional data to determine whether these
interactions are biologically relevant in the TME.

THE LANDSCAPE OF VISTA THERAPEUTICS IN RESEARCH AND DEVELOPMENT
Numerous preclinical and clinical studies are underway to evaluate the activities of VISTA-based
therapeutics [Table 2]. There are numerous drugs of interest in preclinical development, including VISTA
[90]
[91]
mAbs PMC-309 by PharmAbcine , VTX-0811 by Verseau , and KVA12.1 by Kineta , SNS-101 , and
[89]
[88]
INT-18 .
[92]