VISTA expression associated with CD8 confers a favorable immune microenvironment and better overall survival in hepatocellular carcinoma

Abstract

BackgroundHepatocellular carcinoma (HCC) often arises in the setting of chronic inflammation with multiple inhibitory immune signals. V-domain Ig suppressor of T cell activation (VISTA) is identified as a novel negative checkpoint regulator. This study sought to determine the expression and prognostic value of VISTA in HCC and classify tumor microenvironments (TMEs) based on VISTA and CD8+ tumor-infiltrating lymphocytes (TILs).MethodsThe expression of VISTA and CD8 proteins was assessed in 183 HCC tissue microarrays (TMAs) by immunohistochemistry (IHC). VISTA and CD8A mRNA extracted from 372 patients with HCC in The Cancer Genome Atlas (TCGA) database was included as a validation cohort. Associations between the VISTA, clinicopathological variables, and survival were analyzed.ResultsVISTA expression was detected in 29.5% HCC tissues, among which 16.4% tissues were positive for tumor cells (TCs), and 16.9% tissues were positive for immune cells (ICs). VISTA expression was significantly associated with tissues with a high pathological grading (p = 0.038), without liver cirrhosis (p = 0.011), and with a high density of CD8 + TILs (p < 0.001). Kaplan-Meier curves demonstrated that patients with VISTA-positive staining in TCs (p = 0.037), but not in ICs, (p = 0.779) showed significantly prolonged overall survival (OS) than those with VISTA-negative expression. Classification of HCC TME-based VISTA and CD8 + TILs showed 4 immune subtypes: VISTA+/CD8+ (16.9%), VISTA+/CD8- (12.6%), VISTA-/CD8+ (16.4%), and VISTA-/CD8+ (54.1%). The dual positive VISTA+/CD8+ subtype showed significantly prolonged OS than other subtypes (p = 0.023).ConclusionsVISTA protein expression in HCC showed cell specific and displayed different prognosis. VISTA expression was significantly associated with CD8 + TILs, Dual positive VISTA+/CD8+ showed favorable TME and better OS.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4435-1) contains supplementary material, which is available to authorized users.

VISTA expression is associated with a favorable prognosis in patients with high-grade serous ovarian cancer

“…The discrepancy between these studies may be attributed to the use of different VISTA antibodies and variable sample sizes with distinct stages and pathological distributions. Recent studies demonstrated that VISTA expression in TCs (but not ICs) was associated with significantly longer OS in patients with hepatocellular carcinoma and NSCLC [16,21], which correspond to our findings in patients with HGSOC. Contrary to these results, Kuklinski et al reported that VISTA expression in tumor-infiltrating inflammatory cells was correlated with worse disease-specific survival in patients with primary cutaneous melanoma [19].…”

“…We also found that normal human organs other than lymphoid tissues and placental trophoblastic cells did not express VISTA at the protein level [13]. Although VISTA protein has been detected in gastric cancer, oral squamous cell carcinoma, NSCLC, colorectal carcinoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, melanoma, and gestational trophoblastic neoplasia, its expression and relationship with patient survival vary according to the type of cancer [13][14][15][16][17][18][19][20][21]. While VISTA was mainly expressed by tumor-infiltrating lymphocytes, it was only present in 8.8% of gastric cancer cells and in 19.4-22.8% of NSCLC lesions [15,16].…”

“…These studies suggest that VISTA may modulate a novel immune evasion mechanism and is thus a potential target for cancer immunotherapy. VISTA expression in human cancers has been reported in non-small cell lung cancer (NSCLC), hepatocellular carcinoma, colorectal carcinoma, oral squamous cell carcinoma, gastric carcinoma, acute myeloid leukemia, and gestational trophoblastic neoplasia [13][14][15][16][17][18][19][20][21]. Mulati et al also found that VISTA was highly expressed in human ovarian and endometrial cancers [20].…”

VISTA: Coming of age as a multi-lineage immune checkpoint

“…This has been demonstrated in gastric cancer , ovarian cancer , colorectal cancer and primary oral squamous cell mesothelioma . Interestingly, in non‐small‐cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC), tumor cell expression appears to be associated with improved objective survival (OS) . Currently, it is not clear if and how VISTA expression induced in CD45‐negative cells might be supportive for anti‐tumor immunity.…”

Expression and Significance of Immune Checkpoints in Clear Cell Carcinoma of the Uterine Cervix

“…Samples were considered positive for B7-H3 and B7-H4 when ≥5% of the TCs expressing these proteins at any intensity; the 5% cut-off was chosen based on a previous publication [15]. As VISTA expression on TCs and tumourassociated immune cells (TAICs) may have distinct prognostic values [16][17][18], we evaluated the expression of VISTA on these cell types separately. TCs and TAICS were each considered VISTA-positive when ≥5% of them were stained for this protein, as described in previous publications [17,18].…”