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

Ming Zhang,Yu-Fa Li,Xiao-Feng He,Zhong-Yi Dong,Li-Xu Yan,Hua-Jin Pang,Wei Zhao

doi:10.1186/s12885-018-4435-1

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.

Highlights

Hepatocellular carcinoma (HCC) often arises in the setting of chronic inflammation with multiple inhibitory immune signals
We have found that V-domain Ig suppressor of T cell activation (VISTA) expression was significantly correlated with the density of CD8 + tumor-infiltrating lymphocytes (TILs), which implied that VISTA may affect potential signaling in the tumor microenvironment, to recruit T-cell infiltration and subsequently attack the tumor cells (TCs)
We showed that VISTA protein expression in HCC tissues displayed cell-specific and prognostic diversity

Summary

Introduction

Hepatocellular 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. VISTA levels were shown to increase after ipilimumab therapy in patients with prostate cancer [14]. These findings indicated that VISTA probably represented another compensatory inhibitory pathway, after the cancer’s resistance to anti-PD-L1/ (cytotoxic lymphocyte antigen 4) CTLA4 therapy; a combination of VISTA and PD-1/CTLA4 blockade might be a promising new option for cancer treatment. This study investigated the expression of VISTA in HCC tumors and analyzed its association with clinicopathological features, TILs in the tumor microenvironment, and clinical outcomes, which provide the basis for further VISTA blockade immunotherapies in patients with HCC

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Conclusion