Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses

Abstract

V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a negative immune-checkpoint protein that suppresses T-cell responses. To determine whether VISTA synergizes with another immune-checkpoint, programmed death 1 (PD-1), this study characterizes the immune responses in VISTA-deficient, PD-1-deficient (KO) mice and VISTA/PD-1 double KO mice. Chronic inflammation and spontaneous activation of T cells were observed in both single KO mice, demonstrating their nonredundancy. However, the VISTA/PD-1 double KO mice exhibited significantly higher levels of these phenotypes than the single KO mice. When bred onto the 2D2 T-cell receptor transgenic mice, which are predisposed to development of inflammatory autoimmune disease in the CNS, the level of disease penetrance was significantly enhanced in the double KO mice compared with in the single KO mice. Consistently, the magnitude of T-cell response toward foreign antigens was synergistically higher in the VISTA/PD-1 double KO mice. A combinatorial blockade using monoclonal antibodies specific for VISTA and PD-L1 achieved optimal tumor-clearing therapeutic efficacy. In conclusion, our study demonstrates the nonredundant role of VISTA that is distinct from the PD-1/PD-L1 pathway in controlling T-cell activation. These findings provide the rationale to concurrently target VISTA and PD-1 pathways for treating T-cell-regulated diseases such as cancer.

VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML

“…43 It has been shown that VISTA and PD-1 exert non-redundant immune regulatory functions and synergistically regulate T-cell responses. 17 Combined blockade using monoclonal antibodies specific for VISTA and PD-L1 achieved optimal tumor-clearing therapeutic efficacy in murine tumor models. 14 Our data indicate an involvement of both VISTA and PD-1 pathways in the immune evasion in AML, therefore combinational treatment targeting these two inhibitory pathways may lead to a successful leukemia control and improve the clinical outcome.…”

“…Combined inhibition of both VISTA and PD-1 pathways synergistically improves anti-tumor T cell activity. 14,17 These observations suggest a strong therapeutic potential of targeting VISTA for optimal tumor control. To investigate the effect of VISTA on anti-leukemia immune response in AML, we initiated a study using clinical samples collected from AML patients.…”

Coinhibitory Pathways in Immunotherapy for Cancer

“…Anti-VISTA monoclonal antibody also intensified EAE. Synergies between VISTA and PD-1 in regulating T cell tolerance are demonstrated by studies of VISTA/PD-1 and VISTA/PD-L1 double knockout mice, which developed increased frequencies of activated T cells and inflammation compared to single knockout mice, but no spontaneous autoimmunity (152). These findings suggest that combined VISTA and PD-1 blockade may have therapeutic benefits associated with limited adverse events.…”

Multispectral Imaging of T and B Cells in Murine Spleen and Tumor

“…Frozen sections are sometimes used for these sensitive Abs (26), but this results in distorted tissue architecture and artifacts that compromise morphological studies. For these reasons, flow cytometry has long been the gold standard for analysis of immune infiltrates in the tumor microenvironment (27). However, flow cytometry does not provide sufficient contextual information, which was shown, in murine and human studies, to be important in understanding the biological basis of diseases and for predicting outcome in various types of cancer (1,3).…”

“…pmel-1 TCR-transgenic mice were bred to Rag1 2/2 mice to generate pmel TCR/Rag1 2/2 mice. pmel TCR/Rag1 2/2 mice have CD8 + T cells expressing a transgenic TCR specific for mgp100 (25)(26)(27)(28)(29)(30)(31)(32)(33) peptide. TRP1 TCR/Rag1 2/2 -transgenic mice have CD4 + T cells expressing a transgenic TCR specific for mtyrp1 (113)(114)(115)(116)(117)(118)(119)(120)(121)(122)(123)(124)(125)(126)(127) peptide.…”