Page 28 - Read Online

Page 2 of 14 Rabadi et al. J Cancer Metastasis Treat 2022;8:24 https://dx.doi.org/10.20517/2394-4722.2022.06

[1]
predicted to increase by 49% in the United States between 2015 and 2050 . New therapeutic strategies are
necessary to counteract disease burden, particularly in patients whose cancers resist treatment. Today, the
complexity of the tumor microenvironment (TME) is appreciated, and it is well established that the TME
[2]
promotes tumor growth, immune evasion, and resistance to therapies . The TME consists of tumor cells
(TCs), stromal cells (SCs), and immune cells (ICs). These cellular compartments of the TME vary in
patients depending on factors such as cancer type and stage, expression of immune checkpoints, and
treatment resistance. Characterizing the cellular contributions of the TME to tumor progression is critical in
optimizing treatment strategies to overcome resistance and increase patient survival.

Harnessing the immune system for cancer therapies has gained popularity in recent decades. Cancer
immunotherapies include antibodies, cellular therapies, cytokine-based therapies, small molecules, vaccines,
and immune checkpoint inhibitors (ICIs). Targeting the immune system with ICIs yielded stark
improvements in survival rates in preclinical studies, but clinical responses are more modest, in part due to
[2-4]
the highly immunosuppressive TME . This review focuses on the role of the immune checkpoint V-
domain Ig Suppressor of T cell Activation (VISTA) in the TME.

Immune checkpoints can regulate the immune system on multiple levels and are particularly notable in
their regulation of T cell activation to prevent activation-induced damage to tissue. In the highly
immunosuppressive TME, dysfunctional T cells express immune checkpoints . Therefore, current
[5,6]
therapies target these immune checkpoints to relieve T cell suppression . Major pathways targeted by ICIs
[7]
in the clinic include those that target programmed cell death protein-1 (PD-1) and programmed death-
ligand 1 (PD-L1), engaged during exhaustion; and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4),
induced after activation.

While the approval of ipilimumab in 2011, an anti-CTLA-4 monoclonal antibody (mAb) revolutionized
cancer treatment, ICI treatments have shown efficacy in only a subset of patients. A phase III clinical trial
comparing anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab) showed that these drugs are efficacious
in 44% and 19% of patients, respectively, and 58% when used in combination . More than half of patients
[8]
do not respond to immunotherapy at all (primary resistance) or stop responding to ICIs (acquired
resistance). In both cases, their immune systems recognize the cancer but cannot attack it due to the
cancer’s mechanisms of immune evasion (adaptive resistance) . Adaptive resistance can arise after
[2]
treatment with anti-PD-1 and/or anti-CTLA-4 and is associated with an upregulation in the immune
checkpoint V-domain Ig Suppressor of T cell Activation (VISTA) in the TME [9-11] . This indicates that
VISTA may be involved in the development of compensatory mechanisms of adaptive resistance, thus
supporting the need for targeting VISTA to improve therapeutic outcomes.

VISTA has been identified as a key player in regulating T cell activity, as well as in maintaining myeloid
suppressiveness in the TME [12-14] . VISTA was first described as a member of the B7 class of immunoglobulin
[15]
proteins that includes the ligands CD80, CD86 and PD-L1 . In the B7 family, VISTA is most closely
related to PD-L1, with the two immune checkpoints sharing 24% sequence identity . B7 proteins typically
[15]
have both an Ig-V and an Ig-C domain, but VISTA has a single extracellular Ig-V domain, characteristic of
the CD28 family receptor proteins. VISTA’s extracellular domain is unusual compared to other Ig domains
due to its two extra disulfide bonds; a unique charged and extended loop; an additional beta strand; and an
extra helix in the positively charged face of VISTA’s extracellular domain [16,17] .

VISTA is widely expressed in the TME, including on TCs, SCs, and ICs. VISTA expression on TCs varies
greatly depending upon the cancer type . VISTA is broadly expressed in multiple IC lineages [Figure 1],
[18]