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Rabadi et al. J Cancer Metastasis Treat 2022;8:24 https://dx.doi.org/10.20517/2394-4722.2022.06 Page 7 of 14

improve cancer therapies.

In mice bearing B16OVA melanoma tumors, VISTA blockade using the VISTA antagonist monoclonal
antibody 13F3 results in enhanced T cell activation and increased anti-tumor responses via recruitment of
[9]
immune cells to the TME . 13F3 has also been shown to have anti-tumor effects on other tumors, including
the bladder tumor model MB49 and B16BL6 melanoma model . In the GL261 glioma tumor model,
[9]
+
VISTA-induced reduction of disease burden in a CD4 T cell-dependent manner, as shown by CD4
depletion experiments . Remarkably, the combination of anti-VISTA and a single dose of a peptide
[20]
vaccine resulted in an even greater reduction of tumor burden . The authors suggest that high VISTA
[9]
expression on myeloid cells within the TME results in effector T cell suppression, as well as recruitment of
immunosuppressive Tregs and M-MDSC to the TME [Figure 2] . Tregs, a major contributor to immune
[9]
suppression during cancer, can also be modulated by VISTA targeting . Upon adoptive transfer of OTIIs
[9]
[9]
+
into B16OVA-bearing mice, CD4 conversion to Tregs was reduced in mice that received 13F3 . Targeting
VISTA in tumors therefore may have a direct effect on T cell activity and recruitment, as well as display an
indirect effect on T cells via MDSCs or induced Treg differentiation .
[70]
PD-1 and CTLA-4 are important checkpoint regulators of the immune system currently being targeted for
cancer therapies in the clinic. These pathways work in a non-redundant manner on T cells compared to
+
VISTA [23,28] . Studies comparing the changes in T cell effector pathways of tumor-specific CD8 T cells found
that anti-CTLA-4 promotes cell cycle and effector memory responses, while anti-PD-1 enhances
+
[67]
metabolism and effector function . Further, while anti-CTLA-4 induces the expansion of ICOS Th1-like
+
CD4 T cells, anti-PD-1 drives re-expansion of exhausted CD8 T cell subsets . The combination of anti-
[71]
+
PD-1 and anti-CTLA-4 promotes progenitor exhausted (Tex-prog) subsets, which are polyfunctional and
retain proliferative capacity [72,73] . While these checkpoints target T cell priming or exhaustion, anti-VISTA
has the unique ability to target naïve T cells, as well as potentially modulate T cell activity indirectly via
[14]
other immune cells present in the TME . VISTA can therefore be used in combination with anti-PD-1 or
anti-CTLA-4 to enhance T cell activity and therapeutic outcomes in a non-redundant manner [Table 1].
[28]
VISTA AND ITS COUNTER-RECEPTORS: THE TME
Multiple ligands are proposed to bind to VISTA, including PSGL-1 , VSIG-3 , syndecan-2 , and even
[75]
[76]
[74]
[77]
VISTA itself , suggesting that - like other B7 proteins - VISTA may have multiple binding partners.
PSGL-1 is an adhesion molecule expressed on innate immune cells such as monocytes, macrophages, and
+
+
[78]
neutrophils . Among adaptive immune cells, PSGL-1 is expressed on CD4 T cells, CD8 T cells, and Th17
cells, and it may play a role in the TME by promoting CD4 T cell exhaustion and negatively regulating T
[79]
+
cells . The PSGL-1/VISTA interaction was first described by Johnston et al. in 2019, where the authors
[80]
reported that PSGL-1 only binds to VISTA under acidic conditions, like those in the TME, via a histidine-
dependent binding interface . Furthermore, lymph nodes have been shown to possess acidic niches to
[74]
suppress their effector functions without impacting initial naïve T cell activation, thus highlighting another
physiological possibility for the pH-dependent PSGL-1/VISTA interaction . Blocking this interaction in
[81]
vitro with a pH-selective VISTA mAb demonstrated an increase in IFNγ production, NFκB
phosphorylation, and CD4 T cell proliferation of human T cells . Though PSGL-1 is a promising
[74]
+
proposed ligand, it is likely that VISTA has additional binding partners due to VISTA interactions being
found elsewhere in the body where higher pH conditions are present.
V-set and immunoglobulin domain-containing protein 3 and V-set and immunoglobulin domain-
containing protein 8 (VSIG-8) are members of the immunoglobulin superfamily and proposed as binding
partners to VISTA [75,82] . However, subsequent studies have not found significant binding of VSIG-8 to