VISTA mediates the progression of myelodysplastic syndrome

Abstract Myelodysplastic syndrome (MDS) is characterized by progressive cytopenias and a substantial risk of transformation to acute myeloid leukemia. Immune dysregulation is central to the pathogenesis of MDS, and immune suppression is often associated with disease progression. However, immunotherapies such as anti-programmed cell death protein-1 therapy have shown limited efficacy in patients, indicating an incomplete understanding of immune suppression in MDS. To better characterize the immune features of MDS, we performed extensive immune phenotyping of MDS patient bone marrow (BM). We demonstrate that V-domain Ig suppressor of T cell activation (VISTA), an inhibitory immune checkpoint, is upregulated in MDS patients by CD34+ blasts and granulocytic myeloid-derived suppressor cells (G-MDSCs) compared to healthy controls, and G-MDSC VISTA expression positively correlates with T cell suppression. In studies employing the NUP98-HOXD13 transgenic MDS mouse model, genetic deletion of VISTA delays the progression of anemia and decreases the rate of death due to severe cytopenias. Assessment of MDS mice reveals that VISTA deletion reduces BM populations of G-MDSCs and reverses the suppression of T cells and macrophages. Together, our findings suggest that VISTA may augment G-MDSC-mediated immune suppression and significantly contribute to ineffective hematopoiesis in MDS.