Department of Cancer Biology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, USA
Stanley Ching-Cheng Huang
Department of Pathology, University Hospitals Cleveland Medical Center, and Case Western Reserve University School of Medicine, Cleveland, OH, USA; Case Comprehensive Cancer Center, Cleveland, OH, USA
Timothy Chan
Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, USA
Stefanie Avril
Department of Pathology, University Hospitals Cleveland Medical Center, and Case Western Reserve University School of Medicine, Cleveland, OH, USA; Case Comprehensive Cancer Center, Cleveland, OH, USA
Li Lily Wang
Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, USA; Corresponding author
Summary: Myeloid-derived suppressor cells (MDSCs) impair antitumor immune responses. Identifying regulatory circuits during MDSC development may bring new opportunities for therapeutic interventions. We report that the V-domain suppressor of T cell activation (VISTA) functions as a key enabler of MDSC differentiation. VISTA deficiency reduced STAT3 activation and STAT3-dependent production of polyamines, which causally impaired mitochondrial respiration and MDSC expansion. In both mixed bone marrow (BM) chimera mice and myeloid-specific VISTA conditional knockout mice, VISTA deficiency significantly reduced tumor-associated MDSCs but expanded monocyte-derived dendritic cells (DCs) and enhanced T cell-mediated tumor control. Correlated expression of VISTA and arginase-1 (ARG1), a key enzyme supporting polyamine biosynthesis, was observed in multiple human cancer types. In human endometrial cancer, co-expression of VISTA and ARG1 on tumor-associated myeloid cells is associated with poor survival. Taken together, these findings unveil the VISTA/polyamine axis as a central regulator of MDSC differentiation and warrant therapeutically targeting this axis for cancer immunotherapy.
