VISTA: A Promising Target for Cancer Immunotherapy?

Figures & data

Figure 1 Molecular structure of VISTA protein and its function at a cellular level.

Notes: Vista plays a role as ligand on APCs and as receptor on T cells. Modified from Tagliamento M, Bironzo P, Novello S. New emerging targets in cancer immunotherapy: the role of VISTA. ESMO Open. 2019;4:e000683.¹⁷ © 2020 The Authors. Creative Commons CC-BY-NC 

Abbreviations: APC, antigen-presenting cell; TCR, T-cell receptor; MHC, Major Histocompatibility Complex.

Table 1 Selection of Published Studies Evaluating the Role of VISTA in Solid and Hematological Malignancies

Tumor Type	Studies	Research Object	VISTA Expression	Main Findings
Melanoma	Blando et al^Citation48	Melanoma samples (n=44) (comparison with pancreatic tumor samples)	Immune cells by IHC	Higher density of CD68+ macrophages in the tumoral component of melanoma vs pancreatic tumous. Melanoma had significantly lower density of VISTA expression compared to pancreatic tumors.
	Xu et al^Citation38	B16-BL6 murine melanoma cells	Immune cells by IHC	Blocking VISTA augmented the ability of myeloid suppressor cells to produce proinflammatory mediators and diminished their T cell–suppressive functions.
	Rosenbaum et al^Citation37	Melanoma cells	Tumor cells by IHC	The BRAF-regulated transcription factor FOXD3 negatively regulated VISTA expression.
	Liu et al^Citation30	Mice models inoculated with B16BL6 melanoma cells	NA	Mice treated with both VISTA and PD-L1 mAbs had significantly suppressed tumor growth and survival advantage, whereas single mAb treatment was largely ineffective.
	Kakavand et al^Citation39	Melanoma samples (n=34)	Immune cells by IHC	Significant increase in density of VISTA+ lymphocytes from pre-treatment biopsies to progression (12/18) (p = 0.009).
	Kuklinski et al^Citation40	Melanoma samples (n=85)	Immune cells and tumor cells by IHC	The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis (hazard ratio = 3.57, p = 0.005) and multivariate analysis (hazard ratio = 3.02, p = 0.02).
Thoracic cancers	Villaroel-Espindola et al^Citation41	Samples of NSCLC (n=758)	Immune and tumor cells by multiplex quantitative immunofluorescence	VISTA protein was detected in 99% of NSCLC with expression in tumor and stromal cells in 21% and 98% of cases, respectively.
	Brcic et al^Citation42	Samples of lung adenocarcinoma (n=22) or squamous cell carcinomas (n=27) from therapy-naïve patients and BAL samples (n = 17) from patients with lung cancer	Immune cells and tumor cells by IHC	In 13/66 cases (19.7%), 10–70% of lymphocytes expressed VISTA. Significant correlation was seen between VISTA-positive lymphocytes and high T-reg tumors (p = 0.005).
	Chung et al^Citation81	Samples of mesothelioma (n=124) and of NSCLC (n=553)	Tumor cells by IHC	VISTA expression was higher in epithelioid type mesothelioma (p < 0.001). No VISTA expression was observed in tumor cells of NSCLC.
	Muller et al^Citation44	Samples of pleural mesothelioma (n=319) from immunotherapy-naïve patients and samples of benign pleura (n=10)	Immune cells and tumor cells by IHC	85% of 319 samples expressed VISTA. Median VISTA score was higher in epithelioid (50%) subtype vs biphasic (20%) and sarcomatoid (0%) (p < 0.001). VISTA was expressed in inflammatory cells in 94% of 317 samples of mesothelioma.
	Rooney et al^Citation45	Samples of malignant pleural mesothelioma (n=160)	Immune cells and tumor cells by IHC	VISTA expression was detected in all MPM cases (n=160), comprising epithelioid (n=101), biphasic (n=38) and sarcomatoid (n=21). VISTA positivity was demonstrated in both tumour and immune cells. Patients with VISTA “high” tumors showed prolonged survival compared to those with VISTA “low” expression in all subtypes (916.5 days vs 274 days, p < 0.0001).
Pancreatic cancer	Blando et al^Citation48	Samples of pancreatic cancer (n=67) (comparison with melanoma samples)	Immune cells by IHC	Pancreatic tumors expressed significantly higher levels of VISTA than melanoma tumors, and VISTA expression was found predominantly on CD68^+ macrophages. Engagement of VISTA diminished cytokine production by T cells isolated from metastatic pancreatic tumors.
	Liu et al^Citation46	Samples of pancreatic cancer	Immune cells and tumor cells by IHC	88% of the patients showed high-density infiltration of immune cells with up-regulated expression of VISTA in cancer tissues. VISTA was minimally expressed in pancreatic cancerous cells and not detectable in normal pancreatic tissues.
	Byers et al^Citation47	Frozen samples of pancreatic cancer (n=23)	Immune cells and tumor cells by IHC	VISTA expression (scored ++): in normal adjacent tissue 4/16 (25%); in tumor tissue 1/15 (7%); in IPMN 1/4 (25%); in chronic pancreatitis 0/4 (0%); other cancer types 0/4 (0%).
Colorectal cancer	Xie et al^Citation49	RNA extracted from colorectal resected tumors and normal tissues (n=32)	RNA sequencing-based gene expression	Colon and rectum adenocarcinomas expressed similar levels of VISTA. VISTA expression levels were significantly reduced in colorectal tumors compared to normal controls (p < 0.01).
	Zaravinos et al^Citation50	TCGA data of colorectal tumor samples (n=72)	IHC and RT-qPCR	VISTA expression was significantly higher in MSI+ colorectal cancers compared to MSS tumors.
Breast cancer	Zong et al^Citation53	Samples of invasive ductal carcinoma of breast (n=919)	Immune cells and tumor cells by IHC	VISTA was expressed on the immune cells of 29.1% (267/919) of the samples and on the tumor cells of 8.2% (75/919) of the samples.
	Xie et al^Citation52	Cells from breast cancer samples (n=14,897) and paired normal cells (n=7,320)	Single-cell RNA-seq analysis of gene expression levels	A higher level of VISTA expression was observed in breast cancer tissue compared to adjacent normal tissue. VISTA expressed highest in breast cancer tissue than other immune checkpoints.
	Cao et al^Citation58	Samples of TNBC (n=254)	Immune cells and tumor cells by IHC	VISTA was expressed on immune cells in 87.8% (223/254) of the samples, and on tumor cells in 18.5% (47/254) of the samples.
	Pilones et al^Citation59	4T1 murine mammary cancer model of metastatic and immune-resistant TNBC	NA	The efficacy of an antibody specific for VISTA was enhanced by focal RT. Cyclophosphamide + RT and dual PD-1/VISTA blockade had superior therapeutic effects, associated with activation of tumor-infiltrating CD8+ T cells and depletion of intratumoral granulocytic myeloid-derived suppressor cells.
Glioma	Flies et al^Citation28	Murine brain glioma model	NA	VISTA-deficient animals were highly resistant to tumor induction in a murine brain glioma model.
Renal Cell Carcinoma	Hong et al^Citation60	Paired tumor and para-tumor tissues from renal cell carcinomas	Analysis of mRNA expression level of C10orf54 (encoding VISTA) by oncoprint and protein analyzed by immunofluorescence	VISTA was mostly expressed on CD45^+ cells in para-tumors and tumors. The expression level of VISTA in para-tumors was significantly lower than that in tumor sections, in line with the expression pattern of VISTA mRNA.
Ovarian and endometrial cancer	Zong e al.^Citation62	Samples of ovarian cancer (n=146) assessed using IHC	Tumor cell by IHC	VISTA was detected in 51.4% of all samples and 46.6% of PD-L1-negative samples; it was expressed in 28.8%, 35.6%, and 4.1% of tumor cells (TCs), immune cells (ICs), and endothelial cells, respectively. VISTA expression in TCs, but not in ICs, was associated with prolonged progression-free and overall survival. The expression of C10orf54 mRNA was associated with prolonged overall survival.
Hematological malignancies	Kim et al^Citation64	VISTA knockout or wild type mice transplanted with murine myeloid leukemia cells (C1498)	NA	Murine tumor cells growth in vivo was diminished in VISTA knockout mice compared to wild-type mice (p < 0.05) and survival significantly improved (p < 0.05).
	Wang et al^Citation65	Blood samples of patients affected by acute myeloid leukemia (n=30)	Tumor and immune cells by immunofluorescence	VISTA was highly expressed on myeloid-derived suppressor cells in the peripheral blood. VISTA expression was significantly higher in patients with newly diagnosed leukemia compared to healthy controls. Knockdown of VISTA by specific siRNA potently reduced the inhibition of CD8 T cell activity.

Abbreviations: IHC, immunohistochemistry; NA, not applicable; NSCLC, non-small-cell lung cancer; BAL, broncho-alveolar lavage; IPMN, intraductal papillary mucinous neoplasm; RT-qPCR, reverse transcription quantitative real-time polymerase chain reaction; RT, radiotherapy; TNBC, triple-negative breast cancer.

Table 2 Clinical Studies of Drugs Targeting VISTA

Clinical Trial Number	Drug	Tumor Type	Phase	Setting	Design	Actual Status	Summary Results
NCT02671955	JNJ-61,610,588	NSCLC, SCLC, head and neck, pancreatic, colorectal, cervical cancer	I	Advanced disease, >1 line	Single-arm, open label	Recruitment stopped in 2017	Results awaited
NCT02812875	CA-170	Solid tumors and lymphoma	I	Advanced disease, >2 line	Single-arm, open label	Enrolment ongoing	- Acceptable safety up to 2400 mg daily dosage - 50% stable disease
CTRI/2017/12/011026	CA-170	NSCLC, HN/oral cavity, MSI-High or dMMR cancers, HL	II	Advanced disease, previously treated with 1–3 lines	Randomized, multiple-arm, open label (comparison between 400 mg vs 800 mg)	Enrolment ongoing (estimated 130 patients)	- 59.5% of CBR - Trend towards higher activity with lower dosage

Abbreviations: NSCLC, non-small-cell lung cancer; SCLC, small-cell-lung cancer; HN, head and neck; MSI, microsatellite instability; dMMR, mismatch repair deficient; HL, Hodgkin lymphoma; CBR, clinical benefit rate.

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