VISTA Is an Immune Checkpoint Molecule for Human T Cells

Lines, J. Louise; Pantazi, Eirini; Mak, Justin; Sempere, Lorenzo F.; Wang, Li; O'Connell, Sam; Ceeraz, Sabrina; Suriawinata, Arief A.; Yan, Shaofeng; Ernstoff, Marc S.; Noelle, Randolph J.

doi:10.1158/0008-5472.can-13-1504

Cited by 379 publications

(368 citation statements)

References 45 publications

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“…The majority of patients carry intermediate (40%) or high risk (56.7%), only 1 patient (3.3%) was categorized with favorable risk. Consistent with previous reports that VISTA is highly upregulated on myeloid-derived cells, 11,15 we observed high expression of VISTA on monocytes (gated on CD45 + CD11b + CD14 hi/lo ) and myeloid leukemia blasts (gated by CD45 int , CD45 versus SSC, Figure 1). Although highly heterogeneous within the cohort, the majority of patients express significant level of VISTA on their MDSCs (mean frequency 54.26 ± 5.016, Figure 1A).…”

Section: Resultssupporting

confidence: 92%

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

et al. 2018

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Treatment of acute myeloid leukemia (AML) remains challenging. Enhancement of anti-tumor responses by blocking negative immune regulators is a promising strategy for novel effective leukemia therapeutics. V-domain Ig suppressor of T-cell activation (VISTA) is a recently defined negative regulator mediating immune evasion in cancer. To investigate the effect of VISTA on anti-leukemia immune response in AML, we initiated a study using clinical samples collected from AML patients. Here we report that VISTA is highly expressed on myeloid-derived suppressor cells (MDSCs) in the peripheral blood of AML patients. Both the frequency and intensity of VISTA expression on MDSCs are significantly higher in newly diagnosed AML than in healthy controls. Importantly knockdown of VISTA by specific siRNA potently reduced the MDSCs-mediated inhibition of CD8 T cell activity in AML, suggesting a suppressive effect of VISTA on anti-leukemia T cell response. Furthermore, we observed a strong positive association between MDSC expression of VISTA and T cell expression of PD-1 in AML. These results support the strategy of VISTA-targeted treatment for AML and underscore the strong potential for combined blockade of VISTA and PD-1 pathways in effective leukemia control.

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Section: Resultssupporting

confidence: 92%

“…Expression of VISTA is restricted to the hematopoietic system and high on myeloid cells 11 . Both antigen presenting cells (APCs) and T cells express VISTA and it exerts functions of ligands as well as receptors 11,15,16 . Interestingly different from the expression pattern of PD-1 ligand, detection of VISTA on tumor cells is minimal.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…Both activated and exhausted T cells express PD-1, with ex-hausted T cells expressing higher and more persistent levels of PD-1 than activated T cells do (68,71,72). Therefore, instead of relying only on the level of expression of PD-1, in the present study, we also determined coexpression of TIM-3 and 2B4 markers of exhaustion on CD8 ϩ T cells, as well as of two newly reported markers of exhaustion, TIGIT and VISTA (36)(37)(38)73). PD-1, TIM-3, 2B4, TGIT, and VISTA were all coexpressed at various levels on CD8 ϩ T cells from TG of CXCL10 Ϫ/Ϫ deficient mice compared to CD8 ϩ T cells from TG of age-and sex-matched WT B6 mice.…”

Section: Discussionmentioning

confidence: 95%

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

Srivastava

Khan

Chilukuri

et al. 2017

J Virol

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Herpes simplex virus 1 (HSV-1) establishes latency within the sensory neurons of the trigeminal ganglia (TG). HSV-specific memory CD8 ϩ T cells play a critical role in preventing HSV-1 reactivation from TG and subsequent virus shedding in tears that trigger recurrent corneal herpetic disease. The CXC chemokine ligand 10 (CXCL10)/CXC chemokine receptor 3 (CXCR3) chemokine pathway promotes T cell immunity to many viral pathogens, but its importance in CD8 ϩ T cell immunity to recurrent herpes has been poorly elucidated. In this study, we determined how the CXCL10/CXCR3 pathway affects TG-and cornea-resident CD8 ϩ T cell responses to recurrent ocular herpesvirus infection and disease using a well-established murine model in which HSV-1 reactivation was induced from latently infected TG by UV-B light. Following UV-B-induced HSV-1 reactivation, a significant increase in both the number and function of HSV-specific CXCR3 ϩ CD8 ϩ T cells was detected in TG and corneas of protected C57BL/6 (B6) mice, but not in TG and corneas of nonprotected CXCL10 Ϫ/Ϫ or CXCR3 Ϫ/Ϫ deficient mice. This increase was associated with a significant reduction in both virus shedding and recurrent corneal herpetic disease. Furthermore, delivery of exogenous CXCL10 chemokine in TG of CXCL10 Ϫ/Ϫ mice, using the neurotropic adeno-associated virus type 8 (AAV8) vector, boosted the number and function of effector memory CD8 ϩ T cells (T EM ) and tissue-resident memory CD8 ϩ T cells (T RM ), but not of central memory CD8 ϩ T cells (T CM ), locally within TG, and improved protection against recurrent herpesvirus infection and disease in CXCL10 Ϫ/Ϫ deficient mice. These findings demonstrate that the CXCL10/CXCR3 chemokine pathway is critical in shaping CD8 ϩ T cell immunity, locally within latently infected tissues, which protects against recurrent herpesvirus infection and disease.IMPORTANCE We determined how the CXCL10/CXCR3 pathway affects CD8 ϩ T cell responses to recurrent ocular herpesvirus infection and disease. Using a wellestablished murine model, in which HSV-1 reactivation in latently infected trigeminal ganglia was induced by UV-B light, we demonstrated that lack of either CXCL10 chemokine or its CXCR3 receptor compromised the mobilization of functional CD8 ϩ T EM and CD8 ϩ T RM cells within latently infected trigeminal ganglia following virus reactivation. This lack of T cell mobilization was associated with an increase in recurrent ocular herpesvirus infection and disease. Inversely, augmenting the amount of

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“…The human and murine VISTA proteins share 90% identity and display similar expression patterns (5). VISTA is constitutively expressed within the hematopoietic compartment, with the highest expression level on myeloid cells and a lower level on CD4 + , CD8 + T cells, and Foxp3 + CD4 + regulatory T cells.…”

mentioning

confidence: 99%

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

Yuan

Chen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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.

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VISTA Is an Immune Checkpoint Molecule for Human T Cells

Cited by 379 publications

References 45 publications

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

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

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

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

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VISTA Is an Immune Checkpoint Molecule for Human T Cells

Cited by 379 publications

References 45 publications

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

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

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 + T EM and CD8 + T RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

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

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CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease