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

• Published in: Cell reports (Cambridge) Vol. 43; no. 1; p. 113661
• Main Authors: Zhang, Keman, Zakeri, Amin, Alban, Tyler, Dong, Juan, Ta, Hieu M., Zalavadia, Ajay H., Branicky, Andrelie, Zhao, Haoxin, Juric, Ivan, Husic, Hana, Parthasarathy, Prerana B., Rupani, Amit, Drazba, Judy A., Chakraborty, Abhishek A., Ching-Cheng Huang, Stanley, Chan, Timothy, Avril, Stefanie, Wang, Li Lily
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.01.2024; Elsevier
• Subjects: Animals; CP: Cancer; CP: Immunology; GM-CSF; Humans; IL-6; MDSC differentiation; Mice; Mice, Knockout; mitochondrial function; Myeloid Cells - metabolism; Myeloid-Derived Suppressor Cells; Neoplasms - pathology; polyamine; Polyamines - metabolism; STAT3; STAT3 Transcription Factor - metabolism; T-Lymphocytes; tumor-associated myeloid cells; VISTA; polyamine; CP: Immunology; mitochondrial function; tumor-associated myeloid cells; VISTA; GM-CSF; CP: Cancer; STAT3; myeloid-derived suppressor cells; IL-6; MDSC differentiation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113661

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. [Display omitted] •VISTA drives MDSC differentiation by sustaining STAT3 activation and polyamine biosynthesis•VISTA promotes MDSC mitochondrial respiration in STAT3- and polyamine-dependent manner•Blocking VISTA in monocytic progenitors improved antitumor immune responses•Correlated expression of VISTA and ARG1 in myeloid cells is prognostic in endometrial cancer Zhang et al. have identified a causal role of an immune checkpoint protein, VISTA, in driving MDSC differentiation by promoting STAT3 activation, polyamine biosynthesis, and mitochondrial respiration. Blocking VISTA in monocytic progenitors reduced MDSCs and improved antitumor immunity. Correlated expression of VISTA and ARG1 is prognostic in human endometrial cancer.