Terminating Cancer by Blocking VISTA as a Novel Immunotherapy: Hasta la vista, baby

Yum, Ji-Eun Irene; Hong, Young‐Kwon

doi:10.3389/fonc.2021.658488

Cited by 24 publications

(11 citation statements)

References 47 publications

(101 reference statements)

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“…When compared to melanoma, pancreatic cancer displays a significantly higher number of VISTA-positive cells [ 7 ]. We and others observed a positive correlation between PD-L1 and VISTA expression, but these two immune checkpoint receptors are not redundant and represent two distinct potential therapeutic targets [ 22 ]. The feasibility of VISTA targeting in clinical practice is yet to be established, but anti-VISTA antibody treatment reduced the metastatic burden in the murine model of pancreatic cancer liver metastases [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Tumor Budding Is an Independent Prognostic Factor in Pancreatic Adenocarcinoma and It Positively Correlates with PD-L1 Expression on Tumor Cells

et al. 2022

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Pancreatic adenocarcinoma is one of the leading causes of cancer-related death in developed countries. Only 15% of patients are candidates for radical surgery, and adequate prognostication may guide proper postsurgical management. We aimed to retrospectively assess the prognostic significance of the immunohistochemical expression of immune checkpoint receptors (PD-L1 and VISTA), markers of systemic inflammation, thrombosis in the tumor area, and the tumor budding in the group of 107 patients diagnosed with pancreatic adenocarcinoma in a single center. The high expression of PD-L1 on tumor cells (TCs) was associated with worse overall survival (OS, p = 0.041, log-rank). On the contrary, high PD-L1 or VISTA on tumor-associated immune cells (TAICs) was correlated with better OS (p = 0.006 and p = 0.008, respectively, log-rank). The joint status of PD-L1 on TCs and TAICs stratified patients into three prognostic groups. The cases with high-grade budding were characterized by higher PD-L1 expression on TCs (p = 0.008) and elevated systemic inflammatory markers. Moreover, budding was identified as the independent prognostic factor in multivariate Cox regression analysis (HR = 2.87; 95% CI = 1.75–4.68; p < 0.001). To conclude, the pattern of PD-L1 and VISTA expression was associated with survival in univariate analysis. Tumor budding accurately predicts outcomes in pancreatic cancer and should be incorporated into routine histopathological practice.

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Section: Discussionmentioning

confidence: 99%

Tumor Budding Is an Independent Prognostic Factor in Pancreatic Adenocarcinoma and It Positively Correlates with PD-L1 Expression on Tumor Cells

et al. 2022

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“…CI-8993 is another antibody targeting VISTA, which is in a phase I clinical trial recruiting 50 relapsed and/or refractory solid tumor patients to evaluate its safety [ 87 ]. In the B16OVA melanoma model and MB49 bladder tumor model, VISTA mAbs show significant therapeutic effect.…”

Section: The Preclinical and Clinical Research Progression Of Igsf11 ...mentioning

confidence: 99%

IGSF11 and VISTA: a pair of promising immune checkpoints in tumor immunotherapy

et al. 2022

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Immunotherapy has become the major treatment for tumors in clinical practice, but some intractable problems such as the low response rate and high rates of immune-related adverse events still hinder the progress of tumor immunotherapy. Hence, it is essential to explore additional immunotherapy treatment targets. In this review, we focus on the structure, expression and expression-related mechanisms, interactions, biological functions and the progress in preclinical/clinical research of IGSF11 and VISTA in tumors. We cover the progress in recent research with this pair of immune checkpoints in tumor immune regulation, proliferation, immune resistance and predictive prognosis. Both IGSF11 and VISTA are highly expressed in tumors and are modulated by various factors. They co-participate in the functional regulation of immune cells and the inhibition of cytokine production. Besides, in the downregulation of IGSF11 and VISTA, both inhibit the growth of some tumors. Preclinical and clinical trials all emphasize the predictive role of IGSF11 and VISTA in the prognosis of tumors, and that the predictive role of the same gene varies from tumor to tumor. At present, further research is proving the enormous potential of IGSF11 and VISTA in tumors, and especially the role of VISTA in tumor immune resistance. This may prove to be a breakthrough to solve the current clinical immune resistance, and most importantly, since research has focused on VISTA but less on IGSF11, IGSF11 may be the next candidate for tumor immunotherapy.

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“…However, in the absence of IFNγ, expression of PD-L1 is likely to be too low to provide an effective target. We suggest that BCG therapy would be most effective when combined with blocking of both the innate (VISTA [3]) and inducible (PD-L1) immune checkpoints. We anticipate the urothelium-derived transcriptomic IFNγ-signature will prove a valuable tool for the design of more efficacious immunotherapy protocols.…”

Section: Manuscriptmentioning

confidence: 99%

“…1C). By contrast, the inhibitory B7 family member VSIR (VISTA) was expressed constitutively by normal human urothelium but has to-date been overlooked in the bladder [3]. This indicates that normal urothelium, and likely its malignant counterpart, is a locally immunosuppressive environment, with induction of PD-L1 by IFNγ acting as a negative feedback loop to prevent runaway inflammation.…”

Section: Manuscriptmentioning

confidence: 99%

The urothelial transcriptomic response to interferon gamma predicts T1 recurrence-free and basal/squamous muscle-invasive bladder cancer survival and better targeted strategies for immune checkpoint blocking

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et al. 2022

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Intravesical Bacillus Calmette-Guérin vaccine (BCG) is an established immunotherapeutic in bladder cancer (BlCa), provoking inflammation leading to tumour-specific immunity. Immune checkpoint blockers such as anti-PD-L1 have potential for enhancing tumour-specific lymphocyte-mediated cytotoxicity in BCG-refractive or advanced disease. In both cases, Interferon-gamma (IFNγ) plays a central role. We investigated the transcriptomic response of normal human urothelium to IFNγ to disentangle mechanisms of BCG and anti-PD-L1 therapy failure. Exposure of differentiated human urothelium to IFNγ resulted in upregulated MHC class I and class II and de novo expression of CXCL9-11 chemokine genes. Normal urothelium expressed only immuno-inhibitory B7 family members: PD-L1 expression was induced by IFNγ, whereas VISTA was expressed constitutively. A urothelial IFNγ response gene set was derived and used for unsupervised clustering of tumours, which predicted longer recurrence-free survival in non-muscle invasive bladder cancer (NMIBC). In muscle invasive bladder cancer (MIBC), the IFNγ-signature split the basal/squamous consensus subtype, with significantly worse overall survival when weak/absent. Normal urothelium has few resident lymphocytes. Tumour cell killing requires recruitment and activation of IFNγ-secreting pro-inflammatory/cytotoxic lymphocytes while surmounting both innate (VISTA) and upregulated (PD-L1) inhibitory mechanisms. This study offers supportive evidence for strategies to enhance immunotherapy via the IFNγ and VISTA/PD-L1 nexus.

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Terminating Cancer by Blocking VISTA as a Novel Immunotherapy: Hasta la vista, baby

Cited by 24 publications

References 47 publications

Tumor Budding Is an Independent Prognostic Factor in Pancreatic Adenocarcinoma and It Positively Correlates with PD-L1 Expression on Tumor Cells

Tumor Budding Is an Independent Prognostic Factor in Pancreatic Adenocarcinoma and It Positively Correlates with PD-L1 Expression on Tumor Cells

IGSF11 and VISTA: a pair of promising immune checkpoints in tumor immunotherapy

The urothelial transcriptomic response to interferon gamma predicts T1 recurrence-free and basal/squamous muscle-invasive bladder cancer survival and better targeted strategies for immune checkpoint blocking

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