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Page 10 of 14 Rabadi et al. J Cancer Metastasis Treat 2022;8:24 https://dx.doi.org/10.20517/2394-4722.2022.06

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example, PDAC is a poorly immunogenic tumor, but the high expression of VISTA on CD68 TAMs and
TCs indicates that this cancer would be a strong candidate for anti-VISTA treatment [40,51] .

Based on these data, VISTA activity in the TME can be modulated. VISTA blockade is especially attractive
in the context of overcoming adaptive resistance, particularly following the use of other ICIs like anti-PD-1
and anti-CTLA-4. As shown in Table 1, numerous studies have shown upregulation of VISTA in ICs after
immune checkpoint blockade. This, combined with the relevance of VISTA expression on TCs and SCs,
suggests that VISTA is an attractive therapeutic target.

VISTA blockade may also be used in conjunction with radiation therapy. A murine glioma model
comparing the effects of radiation on WT mice versus VISTA KO mice demonstrated that the VISTA KO
[20]
mice survived significantly longer than the WT . Another study showed that the combination of VISTA
and PD-1 co-blockade (with cyclophosphamide) with radiation therapy significantly improves tumor
control and overall survival in a mouse model of triple-negative breast cancer . This combination therapy
[101]
approach overcame some of the mechanisms of adaptive resistance discussed earlier, specifically by
depleting MDSCs from the TME, as well as increasing priming and infiltration of tumor specific CTLs to
the TME.

It is worth noting that the clinical trials thus far have mostly shown safety and dose-liming toxicities. While
the risk for immune-related adverse events in combination therapy is higher than that of monotherapy,
preclinical models can be indicative of the extent to which that risk increases. For example, VISTA/PD-1
[28]
double KO mice do not develop overt autoimmune disease , while CTLA-4 KO mice die very young due
to severe inflammation [102,103] . Since the phenotype of the VISTA/PD-1 double KO is relatively benign to that
of the CTLA-4 KO mice, co-blockade of PD-1 and VISTA may be more therapeutically attractive relative to
the co-blockade of PD-1 and CTLA-4 seen clinically.

CONCLUSION
VISTA modulates both immune cell recruitment to the TME and immune cell function within the TME. It
is especially critical to evaluate these subsets in various murine cancer models and in humans, so anti-
VISTA therapy can be tailored to specific cancer type, stage, and immunogenicity. The anti-VISTA
antibodies in clinical trials may also help shed light on the basic biological mechanisms of VISTA and its
potential binding partners. Although detailed studies are required to evaluate the mechanistic role of VISTA
across immune cell subsets in the TME, it is apparent that VISTA plays a key regulatory role in the TME,
and that VISTA antagonism will be especially beneficial in combination therapy approaches to mitigate
adaptive resistance and improve patient outcomes.

DECLARATIONS
Authors’ contributions
Wrote the manuscript: Rabadi D, Sajani A
Critically reviewed the content: Rabadi D, Sajani AA, Lines JL, Noelle RJ
Read and approved the final manuscript: Rabadi D, Sajani AA, Lines JL, Noelle RJ

Availability of data and materials
Not available.