Expression of the Immune Checkpoint Protein VISTA Is Differentially Regulated by the TGF-β1 - Smad3 Signaling Pathway in Rapidly Proliferating Human Cells and T Lymphocytes.

Stephanie Schlichtner,Sabrina Ruggiero,Mateja Prunk,Vadim V Sumbayev,Elizaveta Fasler-Kan,Inna M Yasinska,Steffen M Berger,Nijas Aliu,Janko Kos,Bernhard F Gibbs,N Helge Meyer

doi:10.3389/fmed.2022.790995

Abstract

Immune checkpoint proteins play crucial roles in human embryonic development but are also used by cancer cells to escape immune surveillance. These proteins and biochemical pathways associated with them form a complex machinery capable of blocking the ability of cytotoxic immune lymphoid cells to attack cancer cells and, ultimately, to fully suppress anti-tumor immunity. One of the more recently discovered immune checkpoint proteins is V-domain Ig-containing suppressor of T cell activation (VISTA), which plays a crucial role in anti-cancer immune evasion pathways. The biochemical mechanisms underlying regulation of VISTA expression remain unknown. Here, we report for the first time that VISTA expression is controlled by the transforming growth factor beta type 1 (TGF-β)-Smad3 signaling pathway. However, in T lymphocytes, we found that VISTA expression was differentially regulated by TGF-β depending on their immune profile. Taken together, our results demonstrate the differential biochemical control of VISTA expression in human T cells and various types of rapidly proliferating cells, including cancer cells, fetal cells and keratinocytes.

Highlights

Immune checkpoint proteins play crucial roles in determining the ability of human cancer cells to escape immune surveillance (1, 2)
We found that TGF-β significantly upregulated V-domain Ig-containing suppressor of T cell activation (VISTA) expression in resting Jurkat T cells (Figure 1A) while, in PMA-activated cells, VISTA levels were reduced by exposure to TGF-β compared to the non-treated cells (Figure 1B)
We investigated MCF-7 human epithelial breast cancer cells, where TGF-β was reported to trigger the expression of galectin-9 (3) and discovered that TGF-β was unable to induce even traces of VISTA expression (Figure 1G)

Summary

Introduction

Immune checkpoint proteins play crucial roles in determining the ability of human cancer cells to escape immune surveillance (1, 2). Others were only discovered recently and such mechanisms remain poorly understood This is a very important issue since identification of the optimal targets for immunotherapy of cancer crucially hinges on our understanding of the biochemistry of immune checkpoint pathways responsible for immune escape. We have recently reported that the TGF-β-Smad[3] pathway is involved in regulating galectin-9 expression in human cancer and embryonic cells (3). TGF-β displays both autocrine and paracrine activities and is able to induce its own expression, which is Smad3-dependent as is the expression of galectin-9 (3) In both cancer and embryonic cells, this pathway is self-controlling and self-sustaining. In this work we aimed to study whether the TGF-β-Smad[3] pathway is involved in VISTA expression

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