VISTA.COMP — an engineered checkpoint receptor agonist that potently suppresses T cell–mediated immune responses

Prodeus, Aaron; Abdul-Wahid, Aws; Sparkes, Amanda; Fischer, Nicholas W.; Cydzik, Marzena; Chiang, Nicholas; Alwash, Mays; Ferzoco, Alessandra; Vacaresse, Nathalie; Julius, Michael; Gorczysnki, Reginald M.; Gariépy, Jean

doi:10.1172/jci.insight.94308

Cited by 32 publications

(30 citation statements)

References 28 publications

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“…The importance of this post‐translational modification in dictating VISTA ligand interactions cannot be understated, given that VISTA multimers (including VISTA–Fc) only bind leukocytes under acidic conditions. Indeed, one group reported binding of VISTA multimer binding to a T cell clone under physiological pH , but neither our group nor Johnston et al . were able to reproduce these findings.…”

Section: The Vista Ligand Mysterymentioning

confidence: 58%

VISTA: Coming of age as a multi-lineage immune checkpoint

ElTanbouly

Schaafsma

Noelle

et al. 2020

Clinical and Experimental Immunology

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The immune response is governed by a highly complex set of interactions among cells and mediators. T cells may be rendered dysfunctional by the presence of high levels of antigen in the absence of co-stimulation while myeloid cells may be programmed towards an immunosuppressive state that promotes cancer growth and metastasis while deterring tumor immunity. In addition, inhibitory programs driven by immune checkpoint regulators dampen anti-tumor immunity. The ideal cancer immunotherapy treatment will improve both cross-priming in the tumor microenvironment and relieve suppression by the inhibitory checkpoints. Recently, blockade of programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) has elicited impressive results, but not in all patients, so additional targets are under investigation. V-set immunoglobulin domain suppressor of T cell activation (VISTA) is a novel immunoregulatory receptor that is broadly expressed on cells of the myeloid and lymphoid lineages, and is frequently implicated as a poor prognostic indicator in multiple cancers. Importantly, antibody targeting of VISTA uniquely engages both innate and adaptive immunity. This, combined with the expression of VISTA and its non-redundant activities compared to other immune checkpoint regulators, qualifies VISTA to be a promising target for improving cancer immunotherapy.

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Section: The Vista Ligand Mysterymentioning

confidence: 58%

VISTA: Coming of age as a multi-lineage immune checkpoint

ElTanbouly

Schaafsma

Noelle

et al. 2020

Clinical and Experimental Immunology

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“…To date, the counter-receptor for VISTA has not been formally identified. Although it has been reported that VISTA interacts with itself via homotypic interactions of its ECD 31 or interacts with VSIG3 (IGSF11), 57,58 whether and how these interactions contribute to T cell suppression have not been determined.…”

Section: Vista Is a Critical Regulator Of T Cell-mediated Immune Respmentioning

confidence: 99%

The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation

Xu¹,

Do²,

Malarkannan

et al. 2018

Cell Mol Immunol

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Among various immunoregulatory molecules, the B7 family of immune-checkpoint receptors consists of highly valuable targets for cancer immunotherapy. Antibodies targeting two B7 family co-inhibitory receptors, CTLA-4 and PD-1, have elicited long-term clinical outcomes in previously refractory cancer types and are considered a breakthrough in cancer therapy. Despite the success, the relatively low response rate (20-30%) warrants efforts to identify and overcome additional immune-suppressive pathways. Among the expanding list of T cell inhibitory regulators, V domain immunoglobulin suppressor of T cell activation (VISTA) is a unique B7 family checkpoint that regulates a broad spectrum of immune responses. Here, we summarize recent advances that highlight the structure, expression, and multi-faceted immunomodulatory mechanisms of VISTA in the context of autoimmunity, inflammation, and anti-tumor immunity.

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“… Lymphocyte activation gene-3 (CD223), which downregulates T cell activation via interaction with major histocompatibility class II molecules ( 25 ). V-domain Ig suppressor of T cell activation, which downregulates T cell proliferation and cytokine production via interaction with a putative ligand(s), which remains to be identified ( 26 – 28 ). …”

Section: Alternative Negative Immune Checkpoint Molecules Which May Smentioning

confidence: 99%

Immune Dysregulation in Cancer Patients Undergoing Immune Checkpoint Inhibitor Treatment and Potential Predictive Strategies for Future Clinical Practice

Rapoport

2018

Front. Oncol.

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Realization of the full potential of immune checkpoint inhibitor-targeted onco-immunotherapy is largely dependent on overcoming the obstacles presented by the resistance of some cancers, as well as on reducing the high frequency of immune-related adverse events (IRAEs) associated with this type of immunotherapy. With the exception of combining therapeutic monoclonal antibodies, which target different types of immune checkpoint inhibitory molecules, progress in respect of improving therapeutic efficacy has been somewhat limited to date. Likewise, the identification of strategies to predict and monitor the development of IRAEs has also met with limited success due, at least in part, to lack of insight into mechanisms of immunopathogenesis. Accordingly, considerable effort is currently being devoted to the identification and evaluation of strategies which address both of these concerns and it is these issues which represent the major focus of the current review, particularly those which may be predictive of development of IRAEs. Following an introductory section, this review briefly covers those immune checkpoint inhibitors currently approved for clinical application, as well as more recently identified immune checkpoint inhibitory molecules, which may serve as future therapeutic targets. The remaining and more extensive sections represent overviews of: (i) putative strategies which may improve the therapeutic efficacy of immune checkpoint inhibitors; (ii) recent insights into the immunopathogenesis of IRAEs, most prominently enterocolitis; and (iii) strategies, mostly unexplored, which may be predictive of development of IRAEs.

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VISTA.COMP — an engineered checkpoint receptor agonist that potently suppresses T cell–mediated immune responses

Cited by 32 publications

References 28 publications

VISTA: Coming of age as a multi-lineage immune checkpoint

VISTA: Coming of age as a multi-lineage immune checkpoint

The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation

Immune Dysregulation in Cancer Patients Undergoing Immune Checkpoint Inhibitor Treatment and Potential Predictive Strategies for Future Clinical Practice

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