Shin and Kim et al. demonstrated that VISTA deletion enhanced macrophage and CD8+ T cell infiltration and reduced tumor growth in orthotopic Pan02 and KPC pancreatic mouse tumor models. VISTA deficiency reprogrammed TAMs from a suppressive SPP1+ to a stimulatory CXCL9+ phenotype. CXCL9+ TAMs exhibited enhanced antigen processing and cross-presentation, and increased recruitment of CXCR3+ CD8+ T cells with sustained cytotoxicity and reduced exhaustion. Anti-VISTA plus gemcitabine produced a synergistic antitumor response. In human PDAC datasets, expression of VSIR (encoding VISTA) correlated with immunosuppressive macrophage states.
Contributed by Shishir Pant
ABSTRACT: 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 prolonged survival. Functionally, VISTA deficiency is linked to a shift in tumor-associated macrophages (TAMs) from an immunosuppressive phenotype marked by secreted phosphoprotein 1 (SPP1), to one enriched for C-X-C motif chemokine ligand 9 (CXCL9), indicative of a pro-inflammatory state. This shift is accompanied by enhanced recruitment of CXCR3⁺ CD8⁺ T cells with sustained cytotoxic potential, among which terminal exhaustion-like CD8+ T cell states are less prevalent. Additionally, VISTA-deficient TAMs exhibit increased antigen cross-presentation, further amplifying CD8+ T cell response against tumors. These findings are corroborated by human PDAC data, which reflect similar immune reprogramming trends. By defining the role of VISTA in controlling Cxcl9:Spp1 ratio and modulating CD8⁺ T cell dynamics, this study positions VISTA inhibition as a promising strategy to reshape the TME and potentiate anti-tumor immunity in PDAC.
Author Info: (1) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Wide River Institute of Immunology, Seoul
Author Info: (1) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Wide River Institute of Immunology, Seoul National University, Gangwon, Republic of Korea. Convergence Research Center for Dementia, Seoul National University Medical Research Center, Seoul, Republic of Korea. BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea. (2) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea. (3) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Wide River Institute of Immunology, Seoul National University, Gangwon, Republic of Korea. Convergence Research Center for Dementia, Seoul National University Medical Research Center, Seoul, Republic of Korea. BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea. (4) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. (5) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Wide River Institute of Immunology, Seoul National University, Gangwon, Republic of Korea. BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea. Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. (6) Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea. (7) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea. (8) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. hyunmu.shin@snu.ac.kr. Wide River Institute of Immunology, Seoul National University, Gangwon, Republic of Korea. hyunmu.shin@snu.ac.kr. BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea. hyunmu.shin@snu.ac.kr. Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea. hyunmu.shin@snu.ac.kr. (9) Samsung Precision Genome Medicine Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea. hangrae.kim@skku.edu. Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, Republic of Korea. hangrae.kim@skku.edu. (10) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. dlee5522@snu.ac.kr. Convergence Research Center for Dementia, Seoul National University Medical Research Center, Seoul, Republic of Korea. dlee5522@snu.ac.kr. BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea. dlee5522@snu.ac.kr.
