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VISTA immune-checkpoint blunts radiotherapy induced anti-tumor immune response

ABSTRACT: Radiotherapy (RT) is a cornerstone treatment for cancers like head and neck cancer (HNC), but it can also unintentionally activate immune-suppressive myeloid cells, which may limit its effectiveness. This study explores the role of the immune checkpoint protein VISTA, which is found at high levels on myeloid cells in both mouse and human HNC tumors. RT further increases the number of VISTA-positive myeloid cells in the tumor and bloodstream. Mice lacking VISTA responded better to RT, with their immune cells–especially macrophages and neutrophils–shifting toward anti-tumor behavior, as revealed by single-cell RNA sequencing. Importantly, combining RT with anti-VISTA antibodies significantly shrank tumors in several cancer models (HNC, breast, colorectal), more so than either treatment alone. This combination also boosted the overall immune response, improving T cell activity through reprogramming of myeloid cells. These findings suggest that blocking VISTA could make RT more effective by counteracting immune suppression in the tumor environment.

ORGANISM(S): Mus musculus

PROVIDER: GSE295914 | GEO | 2025/05/29

REPOSITORIES: GEO

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VISTA immune-checkpoint blunts radiotherapy induced anti-tumor immune response

Project description:VISTA immune-checkpoint blunts radiotherapy induced anti-tumor immune response

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VISTA is an activating receptor that binds the proteoglycan Syndecan-2 on monocytes.

Project description:As indicated by its name, V-domain Ig suppressor of T cell activation (VISTA) is thought to primarily serve as an inhibitory protein that limits immune responses. VISTA-antibodies can dampen the effects of several concomitantly elicited activation signals including T cell receptor (TCR) and Toll-like receptor (TLR) activation, but it is currently unclear if VISTA agonism could singly affect immune cell biology. In this study, we discovered two novel agonistic VISTA antibodies and characterized their effects on human peripheral blood mononuclear cells (PBMC) by scRNA/CITE-seq. Both antibodies agonize VISTA in an Fc-functional manner to elicit transcriptional and functional changes in monocytes consistent with activation. We also used pentameric VISTA to identify Syndecan-2 (Sdc2) and several heparan sulfate proteoglycan (HSPG) synthesis genes as novel regulators of VISTA binding to monocytic cells adding further evidence of bidirectional signaling. Together, our study highlights several novel aspects of VISTA biology that have yet to be uncovered in myeloid cells and serves as a foundation for future research.

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VISTA re-programs macrophage biology through the combined regulation of tolerance and anti-inflammatory pathways

Project description:1) BMDMs treated with anti-VISTA under tolerizing and immunizing conditions. 2) Time course analysis of anti-VISTA-induced alterations in human monocytes after anti-VISTA treatment. 3) Time course analysis of anti-VISTA-induced alterations in BMDMs after anti-VISTA treatment. 4) Single cell ATAC-seq of BMDMs tolerized in the presence or IgG or anti-VISTA.

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