VISTA promotes the metabolism and differentiation of myeloid-derived suppressor cells by STAT3 and polyamine-dependent mechanisms

• DOI: 10.1016/j.celrep.2023.113661
• Publication Date: 2024-01-04T00:57:47Z
• Authors: Keman Zhang; Amin Zakeri; Tyler Alban; Juan Dong; Hieu M. Ta; Ajay H. Zalavadia; Andrelie Branicky; Haoxin Zhao; Ivan Juric; Hana Husic; Prerana B. Partha...; Amit Rupani; Judy A. Drazba; Abhishek A. Chakr...; Stanley Ching-Che...; Timothy Chan; Stefanie Avril; Li Lily Wang
• Keywords: Mice, Knockout; STAT3 Transcription Factor; 0301 basic medicine; 0303 health sciences; QH301-705.5; Myeloid-Derived Suppressor Cells; T-Lymphocytes; CP: Immunology; Article; Mice; Neoplasms; Polyamines; Animals; Humans; Myeloid Cells; Biology (General); CP: Cancer

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.