Abstract
LAG-3 is one of the common tumor immune checkpoints. LAG-3 can inhibit the activation and proliferation of T cells, and can also suppress immunity by regulating other immune-related cell functions. FGL1 was recently discovered to be the main ligand of immune checkpoint LAG-3 and play a critical role in the inhibition of T cells. However, the FGL1 expression in circulating tumor cells (CTCs) and its clinical significance in hepatocellular carcinoma (HCC) remain unclear. Therefore, this bioinformatics analysis was performed to assess the expression of FGL1 in various tumors and its association with immune infiltration. After that, CTCs from 109 HCC patients were detected and the immunofluorescence staining was performed (CD45, EpCAM, CK8/18/19, Vimentin, Twist, DAPI and FGL1). Then, we investigated FGL1 expression and EMT of CTCs and analyzed its relationship with patient survival and clinical relevance. Bioinformatic results showed that FGL1 expression was abnormal in various tumor and it was correlated with the infiltration level of several immune cells. FGL1 expression was detected in CTCs of 40 patients (36.7%). The proportion of advanced TNM stage (P<0.001) and distant metastasis(P=0.020) in FGL1 positive patients was higher than that of FGL1 negative patients. In addition, patients with FGL1 positive circulating tumor cells had worse postoperative survival than FGL1 negative patients (p=0.0297). The mixed phenotypic CTC presented a higher level of FGL1 expression than any other types, the number of which also predicted worse prognosis(p=0.0443). We also found that the expression of FGL1 on CTCs was associated with the level of FGL1 in tumor tissues. Of 12 patients receiving PD-1/PD-L1 blockade in a total of 109 cases, 8 out of 10 patients with FGL1 positive CTC showed immunotherapy resistance. It is the first study that suggested FGL1 expression in CTCs as an indicator of the poor prognosis in HCC patients. CTC detection may serve as a promising replacement for determination of tumor tissue FGL1 expression and provide evidence for the application of immunotherapy.
Highlights
Hepatocellular Carcinoma (HCC) is currently ranked the sixth in the world in incidence and the third in mortality among tumors [1, 2]
The differential expression analysis result showed that FGL1 expression level in tumor tissue compared to normal tissue was various among several tumors (Figure 1A)
FGL1 was correlated with the infiltration level of CD8+T cells, monocytes, regulatory T cells (Tregs), carcinoma-associated fibroblasts (CAFs), Neutrophils and Natural killer T cell in various tumors (Figures 1B–G)
Summary
Hepatocellular Carcinoma (HCC) is currently ranked the sixth in the world in incidence and the third in mortality among tumors [1, 2]. The poor overall prognosis of HCC patients is related to advanced stage at diagnosis and the tendency of recurrence. It is reported in the literature that the 5-year recurrence rate after surgery is still as high as 70% [3]. The survival of HCC patients is extremely poor, and new treatments are urgently needed to improve the prognosis of patients. Research on immune checkpoints inhibitors (ICIs) of HCC has made many improvements [4, 5]. Studies have shown that blocking the PD-1/PD-L1 pathway can significantly improve the prognosis of patients with advanced HCC [6,7,8]. The bright prospects and great significance of immunotherapy for HCC can never be overemphasized
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