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Immune-Checkpoint Protein VISTA Regulates Antitumor Immunity by Controlling Myeloid Cell-Mediated Inflammation and Immunosuppression. Cancer Immunol Res 2019 Sep;7(9):1497-1510

Date

07/26/2019

Pubmed ID

31340983

Pubmed Central ID

PMC6726548

DOI

10.1158/2326-6066.CIR-18-0489

Scopus ID

2-s2.0-85071783703 (requires institutional sign-in at Scopus site)   126 Citations

Abstract

Immune-checkpoint protein V-domain immunoglobulin suppressor of T-cell activation (VISTA) controls antitumor immunity and is a valuable target for cancer immunotherapy. This study identified a role of VISTA in regulating Toll-like receptor (TLR) signaling in myeloid cells and controlling myeloid cell-mediated inflammation and immunosuppression. VISTA modulated the polyubiquitination and protein expression of TRAF6. Consequently, VISTA dampened TLR-mediated activation of MAPK/AP-1 and IKK/NF-κB signaling cascades. At cellular levels, VISTA regulated the effector functions of myeloid-derived suppressor cells and tolerogenic dendritic cell (DC) subsets. Blocking VISTA augmented their ability to produce proinflammatory mediators and diminished their T cell-suppressive functions. These myeloid cell-dependent effects resulted in a stimulatory tumor microenvironment that promoted T-cell infiltration and activation. We conclude that VISTA is a critical myeloid cell-intrinsic immune-checkpoint protein and that the reprogramming of tolerogenic myeloid cells following VISTA blockade promotes the development of T cell-mediated antitumor immunity.

Author List

Xu W, Dong J, Zheng Y, Zhou J, Yuan Y, Ta HM, Miller HE, Olson M, Rajasekaran K, Ernstoff MS, Wang D, Malarkannan S, Wang L

Authors

Subramaniam Malarkannan PhD Professor in the Medicine department at Medical College of Wisconsin
Demin Wang PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
B7 Antigens
Cytokines
Disease Models, Animal
Extracellular Signal-Regulated MAP Kinases
Humans
Immune Tolerance
Immunomodulation
Inflammation
Inflammation Mediators
Intracellular Signaling Peptides and Proteins
Melanoma, Experimental
Mice
Mice, Knockout
Myeloid Cells
Myeloid-Derived Suppressor Cells
NF-kappa B
Neoplasms
Signal Transduction
Toll-Like Receptors
Tumor Microenvironment