Immune-Checkpoint Protein VISTA Regulates Antitumor Immunity by Controlling Myeloid Cell–Mediated Inflammation and Immunosuppression

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 TLRmediated activation of MAPK/AP-1 and IKK/NF-κB signaling cascades. At cellular levels, VISTA regulated the effector functions of myeloid-derived suppressor cells (MDSCs) and tolerogenic 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

VISTA Re-programs Macrophage Biology Through the Combined Regulation of Tolerance and Anti-inflammatory Pathways

“…The expression of VISTA by myeloid lineage cells is broad and constitutive. Published studies show that the genetic deletion of VISTA results in heightened steady-state myeloid activation and the production of immune mediators ( 19 , 24 , 76 , 77 ). Therefore, VISTA is a negative checkpoint regulator whose constitutive function is to keep the myeloid compartment immunologically “quiet.” Data presented in this study show that in addition to this constitutive function, VISTA also plays a role during inflammatory challenges to re-program and restrain macrophage inflammatory differentiation through the regulation of factors that control macrophage tolerance and inflammation.…”

Potential Therapeutic Targets of B7 Family in Colorectal Cancer

“…In addition, VISTA has been found to control myeloid cell-mediated inflammation and immunosuppression by reducing the Tolllike receptor (TLR)-mediated activation of the MAPK/AP-1 and IKK/NF-κB signaling cascades. Blocking VISTA augmented pro-inflammatory mediator production and diminished the T cell-suppressive functions of myeloid cells, which resulted in a stimulatory TME and promoted T cell infiltration and activation (54). Moreover, in the CT26 murine CRC model, via HIF1α binding to the VISTA promotor, hypoxia upregulated VISTA expression preferentially on MDSCs, which in turn contributed to MDSC-mediated T cell suppression under hypoxic conditions (49).…”

VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy

“…Kakavand et al also reported that the majority of melanoma patients showed a significantly increased proportion of VISTA+ lymphocytes following either treatment with anti-PD-1 alone or in with ipilimumab compared with the proportion detected prior to treatment [22]. Xu et al used VISTA inhibitors to verify the function of VISTA as an inhibitory immune checkpoint in the B16-BL6 melanoma model [18]. Rosenbaum et al observed that VISTA is expressed in melanoma patient samples and cell lines.…”