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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 5 of 14

Figure 2. The proposed effects of VISTA blockade in the TME. The administration of an anti-VISTA antagonist results in the
recruitment of T cells to the TME, as well as a reduction in chemotaxis of MDSCs and macrophages into the TME. VISTA antagonism
also results in decreased differentiation of MDSCs into TAMS is also decreased; reduced production of suppressive cytokines by
MDSCs and macrophages, resulting in decreased T cell inhibition, and increased production of IFNγ and IL-2. DCs become more
activated and upregulate Erk1/2 and Jnk1/2, potentially regulating the IL-23/IL-17 inflammatory axis. Neutrophil and PMN-MDSC levels
are decreased in the TME by the reduction of chemotaxis after VISTA blockade. Altogether, these effects of VISTA antagonism result in
reduced tumor burden. VISTA: V-domain Ig Suppressor of T cell Activation; TME: tumor microenvironment; MDSCs: myeloid-derived
suppressor cells; TAMS: tumor associated macrophages.

Tumor associated macrophages (TAMs) infiltrate the TME and contribute to tumor cell proliferation,
angiogenesis, and metastasis . VISTA deficiency impairs macrophage chemotaxis, migration, and cytokine
[59]
production [Figure 2] [12,60] . Moreover, VISTA KO macrophages produce high amounts of inflammatory
[12]
cytokines such as CCL2, CCL3, CCL4, and CCL5 at steady state and after LPS stimulation , highlighting
the role of VISTA in macrophage suppressiveness and potential regulatory role of VISTA antagonism of
TAMs in the TME. Interestingly, VISTA agonist induce macrophage tolerance and promote anti-
inflammatory pathways . VISTA deficiency also decreases TAM levels in the TME of CT26 tumor-bearing
[22]
mice, consistent with the data demonstrating that M-MDSCs can differentiate into TAMs [Figure 2] and
potentially inflammatory DCs [12,61] .

VISTA expression is associated with MDSCs in cutaneous melanoma , oral squamous cell carcinoma ,
[39]
[38]
and acute myeloid leukemia , suggesting that these cancers are strong candidates for VISTA blockade. For
[62]
example, expression of VISTA on MDSCs and expression of PD-1 on CD8 T cells, CD4 T cells, and T are
+
+
reg
[62]
positively correlated in acute myeloid leukemia (AML) patients . Blocking this interaction could have a
therapeutic impact by alleviating MDSC suppressiveness and enhancing T cell responses. Together, these
data support that VISTA expression on MDSCs modulates the TME, and that VISTA blockade has
therapeutic benefits, particularly in the context of adaptive resistance.
Another myeloid cell subset that expresses VISTA is monocytic-DCs (mDCs), which are associated with
cancer inflammation and can arise as a result of M-MDSC differentiation. VISTA antagonism in the B16F10
melanoma model increases the activation state of DCs, resulting in increased expression of CD80 and
[9,63]
MHCII, as well as increased production of cytokines such as IL-12p40 and TNFα . VISTA may also