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Page 4 of 14 Rabadi et al. J Cancer Metastasis Treat 2022;8:24 https://dx.doi.org/10.20517/2394-4722.2022.06

[46]
[40]
PDAC , non-small cell lung cancer [33,45] and high-grade serous ovarian cancer .
While VISTA expression is predominantly immune associated (as discussed later in the review), recent
studies have highlighted that in some cancers, VISTA may be expressed outside of the hematopoietic
compartment on either TCs or SCs (including adipocytes, endothelial cells, fibroblasts, and stellate cells).
Expression of VISTA on TCs is positively associated with patient outcome in ovarian cancer ,
[34]
[30]
[31]
hepatocellular carcinoma , and NSCLC , while in colorectal cancer and gastric cancer , no link with
[33]
[47]
objective survival was observed.
On the other hand, VISTA expression on vascular endothelial cells is associated with lymph node metastasis
in cervical and ovarian cancer . Beyond their association with poor prognosis, SCs have been associated
[48]
[34]
with influencing ICs in the TME . Melanoma-associated fibroblasts had increased VISTA expression
[49]
relative to fibroblasts isolated from noncancerous intact edges of the tumor, and they can interfere with
intracellular CTL signaling . Additionally, distribution of immune cell infiltration in tumor versus stromal
[50]
[51]
regions of the TME can vary depending on the tumor, potentially impacting therapeutic response . Much
like VISTA expression on ICs, the role of VISTA in non-hematopoietic cells such as TCs and SCs likely
varies between cancer types and patients, so further studies are required to determine which markers might
be positive indicators for VISTA antagonism.

For cancers in which VISTA expression is a positive prognostic factor, VISTA blockade may still have
therapeutic benefits. Much like PD-L1 expression , negative suppressive impact of VISTA within the TME
[52]
[42]
could be masked by the positive association with immune infiltration . Even in tumors where VISTA
[53]
expression is low or not directly associated with prognosis or survival—such as oral squamous sarcoma ,
ovarian cancer , prostate cancer, and renal cell carcinoma —VISTA blockade may propel the TME from
[54]
[35]
a “cold” tumor with poor IC infiltration, to become a “hot” tumor with high IC infiltration.
THE ROLE OF VISTA ON MYELOID CELLS
Myeloid cells highly express VISTA, differentiating VISTA from other immune checkpoints. Notably,
VISTA expression on myeloid cells in the TME is much higher than that of myeloid cells in the periphery
[Figure 1]. VISTA is highly expressed on monocytes and regulates monocyte migration and activation. One
pathway that is responsible for this is the CCL2/CCR2 axis, which recruits inflammatory monocytes to the
TME, thus playing a critical role in cancer development and metastasis . In splenic monocytes and bone-
[55]
marrow derived-monocytes from VISTA-deficient mice, surface expression of CCR2 is significantly
[12]
reduced, thus impairing monocyte migration . VISTA may therefore regulate monocyte recruitment to the
TME via the CCL2/CCR2 axis. VISTA could also be regulating monocytes through other inflammatory
pathways, such as the NFκB1 pathway that is significantly downregulated in human monocytes after
treatment with a VISTA agonist .
[22]
A potential mechanism for anti-PD-1 or anti-CTLA-4 treatment failure is MDSC escape mechanisms. Such
escape mechanisms include MDSC accumulation, activation, trafficking, and T cell inhibition [56,57] . In the
B16 OVA model, MDSC levels decrease in mice treated with an antagonistic VISTA mAb known as 13F3
[Figure 2] . Furthermore, adoptive transfer experiments of dye-labeled WT and VISTA KO MDSCs into
[9]
[58]
WT tumor-bearing mice show reduced migration of M-MDSCs from VISTA KO mice to the TME .
Further studies show that M-MDSCs upregulate VISTA under hypoxic conditions and define HIF1α as a
[58]
key transcriptional activator of VISTA . Subsequent experiments also demonstrate that under hypoxic
conditions, VISTA KO MDSCs promote higher levels of CD4 and CD8 T cell proliferation and activation
+
+
[9]
compared to WT MDSCs .