ORCID
- Shilpa Chokshi: 0000-0003-1735-8538
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.
DOI Link
Publication Date
2025-04-28
Publication Title
Cancer Letters
Volume
616
ISSN
0304-3835
Acceptance Date
2025-02-19
Deposit Date
2025-04-29
Funding
We thank Diamond Light Source for access to the B23 beamline and funding projects SM24509, SM20755, and SM21202). This work was also supported by a Swiss Batzeb\u00E4r grant (to EF-K and SB) and Chinese Council PhD Scholarship (XL).
Keywords
Tumor Microenvironment/immunology, Humans, MAP Kinase Kinase Kinases/metabolism, B7 Antigens/metabolism, Signal Transduction, Cell Line, Tumor, Neoplasms/immunology
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Abooali, M., Schlichtner, S., Lei, X., Aliu, N., Ruggiero, S., Loges, S., Ziegler, M., Hertel, F., Volckmar, A., Stenzinger, A., Christopoulos, P., Thomas, M., Klenova, E., Meyer, N., Boussios, S., Heaton, N., Zen, Y., Zamalloa, A., Chokshi, S., Urbani, L., Richard, S., Kirubendran, K., Hussain, R., Siligardi, G., Cholewa, D., Berger, S., Yasinska, I., Fasler-Kan, E., & Sumbayev, V. (2025) 'Intracellular and extracellular activities of V-domain Ig-containing suppressor of T cell activation (VISTA) modulated by immunosuppressive factors of tumour microenvironment', Cancer Letters, 616. Available at: 10.1016/j.canlet.2025.217581
