Intracellular and extracellular activities of V-domain Ig-containing suppressor of T cell activation (VISTA) modulated by immunosuppressive factors of tumour microenvironment

V-domain Ig-containing suppressor of T cell activation (VISTA) is a unique immune checkpoint protein, which was reported to display both receptor and ligand activities. However, the mechanisms of regulation of VISTA activity and functions by factors of tumour microenvironment (TME) remain unclear and understanding these processes is required in order to develop successful personalised cancer immunotherapeutic strategies and approaches. Here we report for the very first time that VISTA interacts with another immune checkpoint protein galectin-9 inside the cell most likely facilitating its interaction with TGF-β-activated kinase 1 (TAK1). This process is required for protection of lysosomes, which is crucial for many cell types and tissues. We found that VISTA expression can be differentially controlled by crucial factors present in TME, such as transforming growth factor beta type 1 (TGF-β) and hypoxia as well as other factors activating hypoxic signalling. We confirmed that involvement of these important pathways modulated by TME differentially influences VISTA expression in different cell types. These networks include: TGF-β-Smad3 pathway, TAK1 (TGF-β-activated kinase 1) or apoptosis signal-regulating kinase 1 (ASK1)-induced activation of activating transcription factor 2 (ATF-2) and hypoxic signalling pathway. Based on this work we determined the five critical functions of VISTA and the role of TME factors in controlling (modulating or downregulating) VISTA expression.

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Publication Details

Journal
Cancer Letters
Published
2025-02-20
DOI
https://doi.org/10.1016/j.canlet.2025.217581
Citations
12
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
9.57

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article

Intracellular and extracellular activities of V-domain Ig-containing suppressor of T cell activation (VISTA) modulated by immunosuppressive factors of tumour microenvironment

Elizaveta Fasler‐Kan, Dietmar Cholewa, Martin Ziegler, N. Helge Meyer et al.
12 citations
Cancer Letters
Immune Cell Function and Interaction
9.57
article

Intracellular and extracellular activities of V-domain Ig-containing suppressor of T cell activation (VISTA) modulated by immunosuppressive factors of tumour microenvironment

Elizaveta Fasler‐Kan, Dietmar Cholewa, Martin Ziegler, N. Helge Meyer, Maryam Abooali, Sophie Richard, Petros Christopoulos, Vadim V. Sumbayev, Luca Urbani, Shilpa Chokshi, Inna M. Yasinska, Elena Klenova, Giuliano Siligardi, Ane Zamalloa, Nigel Heaton, Stergios Boussios, Steffen Berger, Stephanie Schlichtner, Sabrina Ruggiero, Lei Xi, Nijas Aliu, Yoh Zen, Anna‐Lena Volckmar, Franziska Hertel, Rohanah Hussain, Michael Thomas, Albrecht Stenzinger, Stephanie Loges, Kavitha Kirubendran
article en
12 citations

Abstract

V-domain Ig-containing suppressor of T cell activation (VISTA) is a unique immune checkpoint protein, which was reported to display both receptor and ligand activities. However, the mechanisms of regulation of VISTA activity and functions by factors of tumour microenvironment (TME) remain unclear and understanding these processes is required in order to develop successful personalised cancer immunotherapeutic strategies and approaches. Here we report for the very first time that VISTA interacts with another immune checkpoint protein galectin-9 inside the cell most likely facilitating its interaction with TGF-β-activated kinase 1 (TAK1). This process is required for protection of lysosomes, which is crucial for many cell types and tissues. We found that VISTA expression can be differentially controlled by crucial factors present in TME, such as transforming growth factor beta type 1 (TGF-β) and hypoxia as well as other factors activating hypoxic signalling. We confirmed that involvement of these important pathways modulated by TME differentially influences VISTA expression in different cell types. These networks include: TGF-β-Smad3 pathway, TAK1 (TGF-β-activated kinase 1) or apoptosis signal-regulating kinase 1 (ASK1)-induced activation of activating transcription factor 2 (ATF-2) and hypoxic signalling pathway. Based on this work we determined the five critical functions of VISTA and the role of TME factors in controlling (modulating or downregulating) VISTA expression.

Cancer LettersVol. 616
University of Essex (GB), University of Bern (CH), Carl von Ossietzky Universität Oldenburg (DE), King's College - North Carolina (US), Medway School of Pharmacy (GB), University of Kent (GB), Heidelberg University (DE), University Hospital of Bern (CH), University Hospital Heidelberg (DE), Diamond Light Source (GB), Foundation for Liver Research (GB), Klinikum Oldenburg (DE), National Center for Tumor Diseases (DE), University Children’s Hospital Bern (CH), German Center for Lung Research (DE), King's College Hospital (GB), University Medical Centre Mannheim (DE)
Diamond Light Source
Zero hunger
Openalex Percentile: Top 2%
Immune Cell Function and Interaction
9.57
DOIOpen Access PDFOpenAlex
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