VISTA Drives Pancreatic Tumor Progression Through Modulation of The Tumor-Associated Macrophage Polarity

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies due to its highly immunosuppressive tumor microenvironment (TME), which limits effective therapeutic interventions. Here, we demonstrate that V-domain immunoglobulin suppressor of T cell activation (VISTA) plays a crucial role in orchestrating macrophage polarity within the PDAC TME. Using murine PDAC models, we show that VISTA deficiency markedly impairs tumor growth, leading to reduced tumor volumes and prolonged survival. Mechanistically, VISTA loss reprograms tumor-associated macrophages (TAMs) from an immunosuppressive, secreted phosphoprotein 1(SPP1) expressing phenotype to a pro-inflammatory, C-X-C motif chemokine ligand 9 (CXCL9) expressing subtype. This switch enhances the recruitment of C-X-C motif chemokine receptor 3 (CXCR3) positive CD8+ T cells, reducing their exhaustion and sustaining their cytotoxic activity. Additionally, VISTA-deficient TAMs exhibit increased antigen cross-presentation, further amplifying CD8+ T cell response against tumors. These findings are corroborated by human single cell RNA-seq datasets, which suggest a conserved mechanism of VISTA-mediated immune modulation in PDAC TME. By elucidating the upstream role of VISTA in driving Cxcl9:Spp1 macrophage polarity and T cell dynamics, this study highlights VISTA inhibition as a promising therapeutic strategy to reshape the TME, augment CD8+ T cell function, and enhance anti-tumor immunity in PDAC. Overall design: To investigate how VISTA deficiency impacts the immune-oncologic landscape of PDAC, we utilized a syngeneic orthothopic model comparing tumor growth between wild-type (WT) and VISTA-deficient mice. We validated reduction of pancreatic tumor via treatment of anti-VISTA antibody in WT mice. Using anti-CSF1R model, we identified a population that expresses high VISTA expression. We then performed gene expression profiling analysis using data obtained from RNA-seq of pancreatic tumors in WT and Vsir-/- mice on day 28 post-inoculation.