Page 32 - Read Online

Page 6 of 14 Rabadi et al. J Cancer Metastasis Treat 2022;8:24 https://dx.doi.org/10.20517/2394-4722.2022.06

[26]
regulate DCs by suppressing Erk1/2 activation and by inhibiting IL-23 production . Therefore, VISTA
antagonism may reverse immune suppression and enhance anti-tumor responses.

THE ROLE OF VISTA ON GRANULOCYTES
Beyond the previously discussed subsets, VISTA is also expressed on granulocytes, including eosinophils ,
[64]
[63]
[19]
neutrophils , and PMN-MDSCs . Despite being associated with allergic diseases, some tumors display
eosinophilia . Eosinophils express VISTA constitutively at low levels but have been shown to nonetheless
[65]
affect immune responses . In an OVA-induced asthma model, VISTA-deficient mice had significantly
[64]
higher eosinophil levels in the lung compared to WT mice . Another group showed that the use of an
[66]
antagonistic VISTA mAb during antigen challenge induced an eosinophil mediated inflammatory Th2
allergy response. Together, these studies suggest that VISTA blockade may help modulate eosinophils in the
TME to improve patient outcomes.

VISTA also plays a regulatory role in neutrophils. IHC analysis of primary cutaneous melanoma samples
demonstrated that VISTA expression correlates with neutrophil infiltration of the TME and that
[37]
neutrophils were typically associated with tumor ulceration and necrosis . Transcriptional analysis of
-/-
Vsir psoriatic mice demonstrates that neutrophils in these mice may negatively regulate apoptosis and
positively regulate the immune system . These mice also possess increased Cxcl2 expression in the skin
[26]
and increased serum CXCL2 levels. VISTA targeting reduces CXCR2 expression on neutrophils and ablates
migratory responses to CXCL2 . Neutrophil migration is regulated by VISTA, which could thus impact
[67]
both neutrophil and PMN-MDSC levels in the TME.

Indeed, VISTA antagonism significantly reduces PMN-MDSC levels in the TME and spleen in a murine
[9]
B16F10 melanoma model . However, treatment did not decrease suppressive activities of PMN-MDSCs as
it did with M-MDSCs . Though PMN-MDSCs and M-MDSCs are different in origin and function, both
[9]
subsets are suppressive in the TME and tend to be poor prognostic factors in cancer [68,69] . These data indicate
that the PMN-MDSC subset might not directly respond to VISTA blockade alone and can be taken into
consideration when designing a combination therapy approach.

VISTA: A DIRECT AND INDIRECT REGULATOR OF T CELLS IN THE TME
VISTA acts as a negative checkpoint regulator of naïve T cell quiescence and peripheral tolerance . Both
[14]
naïve and memory CD4 and CD8 T cells express VISTA, and multiple studies show that VISTA modulates
+
+
T cell activity [20,23] . Aged VISTA-deficient mice display enhanced T cell activation and cytokine
[23]
-/-
production . VISTA CD4s cultured in vitro with anti-CD3 also exhibit high proliferation and production
of cytokines such as IFNγ, IL-17A and TNFα . Furthermore, plate-bound VISTA Ig inhibits CD4 and
+
[20]
CD8 T cell proliferation and cytokine production, as well as reduces IL-2 production by CD4 memory T
+
+
cells and IFNγ production by CD8 T cells .
+
[15]
+
[14]
Naïve CD4 T cells exhibit VISTA mediated control of quiescence and peripheral tolerance . Single-cell
sequencing of naïve CD4 T cells shows unexpected heterogeneity in the naïve T cell compartment, with
+
VISTA mice showing a loss in a cluster marked by genes involved in T cell quiescence . CD4 T cells are
[14]
+
-/-
[14]
also less tolerized against self-peptides . These data indicate that VISTA alters T cell tolerance, so targeting
VISTA holds promise in modulating T cell tolerance to tumors. The change in tolerance may allow for a
broader repertoire of T cells to be recruited into the TME, resulting in a more robust and broader anti-
tumor immune response. We speculate that VISTA signaling therefore may work in conjunction with TCR
signaling by potentially reducing the threshold of TCR signaling and allowing for lower affinity antigens
with that to induce immune responses. Naïve T cell regulation by VISTA may therefore be utilized to