Expression patterns of programmed death ligand 1 correlate with different microenvironments and patient prognosis in hepatocellular carcinoma

Liu, Chaoqun; Xu, Jing; Zhou, Zhongguo; Jin, Li-Lian; Yu, Xing-Juan; Xiao, Gang; Lin, Jie; Zhuang, Shi‐Mei; Zhang, Yaojun; Zheng, Limin

doi:10.1038/s41416-018-0144-4

Cited by 89 publications

(89 citation statements)

References 55 publications

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“…PD-L1TCs + were detected in 36.4% of HCC when using cut-off value of 5% in our research. Two previous studies report PD-L1TCs + in 29.8% and 19% of HCC cases using the same cut-point, respectively [47,48]. Here,our finding did not observe significant correlation between the expression of PD-L1 on TCs or ICs and survival in multivariate analysis, but a tendency towards improved OS in PD-L1TCs + patients.…”

Section: Discussioncontrasting

confidence: 61%

Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using Multiplex Quantitative Analysis

Guo

Yuan

et al. 2020

Preprint

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Background FGL1-LAG-3 pathway is a promising immunotherapeutic target and has synergistic effect with PD-1/PD-L1. However, the prognostic significance of FGL1-LAG-3 pathway and the correlation with PD-L1 in hepatocellular carcinoma (HCC) remain unkonwn. Method The distributions, associations, and clinical significances of LAG-3, FGL1, PD-L1 and CD8 protein expression in 143 HCC patients were assessed by multiplex immunofluorescence. Results We found FGL1 and LAG-3 densities were elevated while PD-L1 and CD8 were decreased in HCC tissues compared to adjacent normal liver tissues. High levels of FGL1 were strongly associated with high densities of LAG-3 + cells but not PD-L1. CD8 + T cells densities had positive correlation with PD-L1 levels and negative asscociation with FGL1 expression. Elevated densities of LAG-3 + cells and low levels of CD8 + T cells were correlated with poor disease outcome.Moreover,LAG-3 + cells deteriorated patient stratification based on the abundance of CD8 + T cells. Paitents with positive PD-L1 expression on tumor cells (PD-L1TC + ) tended to have a improved survival than that with negative PD-L1 expression on tumor cells (PD-L1TC - ). Futhermore, PD-L1TC - in combination with high densities of LAG-3 + cells showed the worst prognosis, and PD-L1TC + patients with low densities of LAG-3 + cells had the best prognosis. Conclusions LAG-3, FGL1, PD-L1 and CD8 have distinct tissue distribution and relationships with each other. High levels of LAG-3 + cells and CD8 + T cells represent unfavorable and favorable prognostic biomarkers for HCC respectively. Levels of LAG-3 + cells in combination with PD-L1 status on tumor cells have potential to identify patients who may benefit from immune checkpoints blockade combination strategies.

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Section: Discussioncontrasting

confidence: 61%

Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using Multiplex Quantitative Analysis

Guo

Yuan

et al. 2020

Preprint

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“…Eighteen studies determined the mPD-L1 expression in tumor tissues. Among them, 16 studies analyzed the relationship between mPD-L1 expression and OS [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29], seven studies analyzed the relationship between mPD-L1 expression and DFS [14,21,23,25,26,30,31], and six studies analyzed the relationship between mPD-L1 expression and RFS [15,19,20,22,27,28]. Besides, only three studies were conducted in Western countries [20,24,31].…”

Section: Study Characteristicsmentioning

confidence: 99%

“…Besides, only three studies were conducted in Western countries [20,24,31]. The remaining 16 studies were conducted in Asia, of which 12 studies were from China [14,[16][17][18][19]21,22,[25][26][27][28][29]. In particular, Dai et al [26] analyzed data from two independent groups, and both of them were included in this meta-analysis.…”

Section: Study Characteristicsmentioning

confidence: 99%

Prognostic value of programmed cell death ligand 1 (PD-L1) for hepatocellular carcinoma: a meta-analysis

et al. 2020

Bioscience Reports

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The prognostic role of programmed death ligand-1 (PD-L1) expression in hepatocellular carcinoma (HCC) has been widely studied but the results are controversial. In this comprehensive meta-analysis, we elucidated the clinical value of PD-L1 in HCC. Relevant studies were systematically searched in the Cochrane Library, EMBASE, and PubMed until June 27, 2019. Eligible studies were validated for the prognostic effect of PD-L1 on the overall survival (OS), disease-free survival (DFS), and relapse-free survival (RFS) in HCC using a hazard ratio (HR) and its 95% confidence interval (95% CI). Twenty-three studies with 3529 patients were involved in this meta-analysis. The pooled results revealed that high membrane-bound PD-L1 (mPD-L1) expression was associated with poor OS (HR: 1.42; 95% CI: 1.12–1.80; P = 0.004) and had no significant correlation with RFS (HR: 1.14; 95% CI: 0.85–1.54; P = 0.39), and DFS (HR: 1.36; 95% CI: 0.81–2.28; P = 0.25). The results also indicated that high soluble PD-L1 (sPD-L1) levels were associated with worse OS (HR: 2.93; 95% CI: 2.20–3.91; P < 0.00001). In addition, high mPD-L1 expression was associated with high alpha-fetoprotein levels (AFP; OR = 1.46; 95% CI: 1.16–1.84; P = 0.001), hepatitis (OR = 0.72; 95% CI: 0.54–0.98; P = 0.03), poor tumor differentiation (OR = 0.68; 95% CI: 0.55–0.84; P = 0.03), and tumor-infiltrating lymphocytes (OR = 3.39; 95% CI: 1.06–10.91; P = 0.04). The mPD-L1 expression had no significant correlation with age, number of tumors, gender, tumor size, liver cirrhosis, vascular invasion, tumor encapsulation, or TNM stage. The study revealed that high mPD-L1 expression in the tumor tissue and high sPD-L1 levels were associated with shorter OS in HCC. Moreover, overexpression of mPD-L1 was significantly associated with poor tumor differentiation, hepatitis, AFP elevation, and tumor-infiltrating lymphocytes.

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“…A total of 390 patients who received curative resection for HCC at Sun Yat-sen University Cancer Center between 2005 and 2010 were randomly enrolled as previously described. 50 The inclusion criteria used in patient enrollment were the absence of anticancer therapies prior to the operation and availability of followup data. During the follow-up period, 223 patients developed recurrent HCCs and 166 of them received further treatments, HCCs and received post-operative TACE treatment stratified by CD47 expression.…”

Section: Patients and Specimensmentioning

confidence: 99%

Macrophages induce CD47 upregulation via IL-6 and correlate with poor survival in hepatocellular carcinoma patients

Chen

Zheng

et al. 2019

OncoImmunology

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CD47 is known to be involved in phagocyte-mediated tumor clearance; however, its expression, clinical significance, and regulatory mechanism in hepatocellular carcinoma (HCC) remain poorly understood. In the present study, we found that upregulation of CD47 expression on tumor cells was correlated with poor overall survival and recurrence-free survival in patients with HCC. Abundance of macrophages (Mφs) infiltration was found in CD47 + tumor tissues. Mechanistic studies revealed that IL-6 derived from tumorinfiltrating Mφs could upregulate CD47 expression on hepatoma cells through activation of the STAT3 pathway. Neutralization of CD47 or disruption of the IL-6-STAT3 axis reduced the ability of tumor cells to escape phagocytosis. Moreover, CD47 blockade could enhance Mφ-mediated phagocytosis in the presence of chemotherapeutic drugs, and HCC patients with lower CD47 expression were more likely to benefit from adjuvant transcatheter arterial chemoembolization (TACE) treatment. These findings revealed that Mφderived IL-6 was responsible for CD47 expression on hepatoma cells, which might be served as a potential prognostic marker and a predictor for patients who might benefit from adjuvant TACE treatment.

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Expression patterns of programmed death ligand 1 correlate with different microenvironments and patient prognosis in hepatocellular carcinoma

Abstract: Our study provided a novel methodology to evaluate PD-L1 expression in the tumour microenvironment, which might help to select patients who would benefit from anti-PD-1/PD-L1 immunotherapies.

Cited by 89 publications

References 55 publications

Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using Multiplex Quantitative Analysis

Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using Multiplex Quantitative Analysis

Prognostic value of programmed cell death ligand 1 (PD-L1) for hepatocellular carcinoma: a meta-analysis

Macrophages induce CD47 upregulation via IL-6 and correlate with poor survival in hepatocellular carcinoma patients

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