VISTA+/CD8+ status correlates with favorable prognosis in Epithelial ovarian cancer.
Immunotherapy by blocking immune checkpoint regulators has emerged as a new targeted therapy for some cancers. Among them V-domain Ig suppressor of Tcell activation (VISTA) which is identified as a novel checkpoint regulator in ovarian cancer. This study aimed to investigate the VISTA role in Epithelial ovarian cancer (EOC), and its relationship with tumor-infiltrating lymphocytes (TILs) markers and its prognostic value. The expression of VISTA, CD3, CD8, CD4, FOXP3, and CD56 was assessed in 168 EOC tissue microarrays (TMA) by immunohistochemistry (IHC). In addition, associations between VISTA, TILs, clinicopathological variables, and overall survival (OS) were analyzed. VISTA expression in IGRov1 cells, as well as in PBMC of EOC patient, was evaluated by western blot. VISTA expression was detected in 64,28% of tissues, among which 42.3% were positive for tumor cells (TCs), and 47,9% were positive for immune cells (ICs). In univariate analysis, VISTA expression was significantly associated with a high density of TILs:CD3+ (p = 0,001), CD4+ (p = 0,002) and CD8+ (p≤0,001), in ICs but not in TCs. In terms of OS, multivariate analysis showed a significant association between the high density of CD8+ TILs and VISTA positive staining in ICs (p = 0,044), but not in TCs (p = 0,108). Kaplan-Meier curves demonstrated no correlation between VISTA expression and prolonged OS in both ICs (p = 0,841) and TCs (p = 0,090). Classification of EOC tumor microenvironment based on VISTA and CD8+TILs expression, demonstrated four immune subtypes: VISTA+/CD8+, VISTA+/CD8-, VISTA-/CD8+ and VISTA-/CD8-. The dual positive VISTA+/CD8+ subtype was significantly associated with prolonged OS in both TCs and ICs (p = 0,012 and p≤0,01, respectively), whereas patients with VISTA+/CD8- had the worst OS. Our results showed that VISTA is highly expressed in the IGRov1 cell line and LT-CD8 from a patient with EOC. Our results highlighted the association of VISTA expression and CD8+ TILs in EOC, with prolonged OS in patients with VISTA+/CD8+ and proposed VISTA as a potential immunotherapeutic target in EOC.
Jlassi A
，Manai M
，Morjen M
，Sahraoui G
，Elasmi Allal M
，ELBini-Dhouib I
，Naija L
，Charfi L
，Rejaibi R
，Ben Ahmed M
，Marrakchi N
，Srairi-Abid N
，Mezlini A
，Manai M
，Mrad K
，Doghri R
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《PLoS One》
Liver-infiltrating CD8(+) lymphocytes as prognostic factor for tumour recurrence in hepatitis C virus-related hepatocellular carcinoma.
Chronic liver inflammation and immune/inflammatory response promote hepatocellular carcinoma. The aim of this study was to characterize the immune status of HCV-related cirrhosis in patients with hepatocellular carcinoma (HCV-HCC) as compared to HCV patients without hepatocellular carcinoma.
Immune markers (CD3, CD4, CD8, CD20, CD56, TCRγδ, FoxP3) and gene expression profiles (CD8α, CD8β, FoxP3, IL-6, IFN-γ, perforin, RANTES) were analysed in a test cohort by immunohistochemistry and quantitative RT-PCR analysis on serial non-tumorous and tumorous tissues.
Immune micro-environment was more inflammatory in HCV-HCC than HCV cirrhotic livers. The number of CD3(+) , CD4(+) , CD8(+) and CD20(+) liver-infiltrating lymphocytes was significantly higher, whereas the number of CD56(+) cells was significantly lower in HCV-HCC compared to HCV cirrhotic parenchyma. These differences were restricted to fibrous septa for CD4(+) and CD20(+) cells and to nodular parenchyma for CD8(+) cells. Gene expressions of CD8α, FoxP3 and RANTES were also significantly higher in HCV-HCC than in HCV cirrhosis. Interestingly, in a large cohort of 63 HCV-HCC patients. The number of CD8(+) cells ≥100/field was associated with significant higher tumour recurrence (P = 0.003) and lower overall survival (P = 0.05) at 5 years.
High densities of liver-infiltrating lymphocytes in HCV-HCC cirrhotic parenchyma prevail inflammatory conditions and could contribute to tumorigenesis and tumour recurrence. These results could contribute towards better clinical evaluation of patients susceptible for HCC recurrence after curative surgery.
Ramzan M
，Sturm N
，Decaens T
，Bioulac-Sage P
，Bancel B
，Merle P
，Tran Van Nhieu J
，Slama R
，Letoublon C
，Zarski JP
，Jouvin-Marche E
，Marche PN
，Leroy V
... -
《-》
Impact of Immune Response on Outcomes in Hepatocellular Carcinoma: Association With Vascular Formation.
We investigated the prognostic value of programmed death ligand 1 (PD-L1) expression, tumor-infiltrating CD8-positive T-cell status, and their combination in hepatocellular carcinoma (HCC). Their association with PD-L1 expression and vascular formation was further explored.
Using a database of 387 patients who underwent hepatic resection for HCC, immunohistochemical staining of PD-L1, CD8, and CD34 was performed. Additionally, we undertook an enzyme-linked immunosorbent assay for soluble PD-L1. Compared with patients with HCC and PD-L1-negative expression (n = 311), patients with HCC and PD-L1-positive expression (n = 76) showed significantly worse overall survival (OS; multivariate hazard ratio, 2.502; 95% confidence interval [CI], 1.716-3.649; P < 0.0001). The presence of tumor-infiltrating CD8-positive T cells was significantly correlated with longer OS (multivariate hazard ratio, 0.383; 95% CI, 0.274-0.537; P < 0.0001). Stratification based on PD-L1 expression in cancer cells and tumor-infiltrating CD8-positive T-cell status was also significantly associated with OS (log-rank, P < 0.0001). HCC with PD-L1-positive expression was significantly correlated with positivity for vessels that encapsulated tumor clusters. Serum PD-L1 levels were significantly higher in the group of patients who had PD-L1-positive expression than in the group of patients who had PD-L1-negative expression (P = 0.0158).
PD-L1 expression in cancer cells was associated with a poor clinical outcome and vascular formation in patients with HCC. Additionally, the combination of PD-L1 expression with tumor-infiltrating CD8-positive T-cell status enabled further classification of patients based on their clinical outcome. Thus, PD-L1 expression in cancer cells and tumor-infiltrating CD8-positive T-cell status might serve as predictive tissue biomarkers.
Itoh S
，Yoshizumi T
，Yugawa K
，Imai D
，Yoshiya S
，Takeishi K
，Toshima T
，Harada N
，Ikegami T
，Soejima Y
，Kohashi K
，Oda Y
，Mori M
... -
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