# Immunosuppressive immune microenvironment landscapes in VISTA-high gastric cancer

## TL;DR

This study explores how high VISTA expression in gastric cancer creates an immunosuppressive environment, leading to poor treatment outcomes and suggesting VISTA as a potential target for immunotherapy.

## Contribution

The study identifies VISTA as a central immunoregulatory checkpoint in gastric cancer and reveals its role in promoting T cell exhaustion and immunosuppression.

## Key findings

- High VISTA expression correlates with an immunosuppressive TME marked by exhausted CD8+ T cells, Tregs, M2-like macrophages, and CAFs.
- Elevated VISTA levels are linked to worse immune-related progression-free survival in patients treated with immune checkpoint inhibitors.
- VISTA+ macrophages promote T cell exhaustion via the LGALS9-PTPRC signaling axis and show enhanced antigen-presenting capacity.

## Abstract

V-domain Ig-containing suppressor of T cell activation (VISTA) is an immune checkpoint molecule predominantly expressed on myeloid cells and has recently been recognised as a key mediator of immunosuppression within the tumour microenvironment (TME). However, its expression pattern in gastric cancer and the functional characteristics of the VISTA-high TME remain poorly understood.

We conducted multiplex immunohistochemistry on tumour samples from 172 patients to characterise the immune landscape of the VISTA-high tumour microenvironment. Additionally, single-cell RNA sequencing (n = 17) and spatial transcriptomics (n = 3) were employed to delineate the cellular expression patterns of VISTA and investigate the potential immunomodulatory functions of VISTA-expressing macrophages.

High VISTA expression was associated with an immunosuppressive TME characterised by increased infiltration of exhausted CD8+ T cells, regulatory T cells (Tregs), M2-like macrophages, and cancer-associated fibroblasts (CAFs). Moreover, elevated VISTA levels in the tumour region were linked to worse immune-related progression-free survival (irPFS) in patients treated with immune checkpoint inhibitors (ICIs). Mechanistically, VISTA+ monocyte-macrophage (MoMac) populations promoted T cell exhaustion via the LGALS9-PTPRC signalling axis and exhibited enhanced antigen-presenting capacity.

Our findings establish VISTA as a central immunoregulatory checkpoint in gastric cancer, suggesting its potential as a promising therapeutic target for combination immunotherapeutic approaches.