VISTA drives tumour-intrinsic proliferation in mesothelioma cells.

Abstract

Background: Mesothelioma is a therapeutic challenge because current therapies have limited efficacy. In this study, we investigated the role of the immune checkpoint molecule V-domain Ig suppressor of T cell activation (VISTA) in mesothelioma cells.

Methods: The effect of VISTA expression on cell proliferation was analysed using mesothelioma cell lines and a mouse xenograft model. To investigate the underlying mechanisms, we performed immunoprecipitation-mass spectrometry and RNA-seq analysis to identify VISTA-associated proteins and downstream transcriptional changes.

Results: Analysis of The Cancer Genome Atlas (TCGA) dataset revealed that VISTA and B7-H3 were highly expressed in mesothelioma cells; their expression patterns were positively correlated with those of genes highly expressed in epithelioid and sarcomatoid cells, respectively. Functional studies revealed that VISTA overexpression enhanced proliferation of mesothelioma cell lines, whereas VISTA knockdown markedly suppressed tumour growth in vitro and in vivo. Proteomic profiling revealed interactions between VISTA, cell adhesion molecules and intracellular signalling proteins such as receptor-interacting serine/threonine-protein kinase 1 (RIPK1), whereas RNA sequencing revealed enrichment of TNF signalling, and functional analyses demonstrated enhanced AKT phosphorylation.

Conclusions: These findings indicate that VISTA promotes mesothelioma cell proliferation through tumour-intrinsic signalling independent of immune modulation. VISTA is a promising subtype-specific therapeutic target for mesothelioma.