Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using multiplex quantitative analysis

Guo, Mengzhou; Yuan, Feifei; Feng, Qi; Sun, Jialei; Rao, Qianwen; Zhao, Zhiying; Huang, Peixin; Fang, Tingting; Yang, Biwei; Xia, Jinglin

doi:10.1186/s12967-020-02469-8

Cited by 104 publications

(74 citation statements)

References 53 publications

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“…LAG-3 expression leads to dampened CD4+ T cell activation, enhanced Treg suppressor activity, and decreased cytotoxic CD8+ T cell function [ 33 ]. LAG-3 expression has been demonstrated to be associated with reduced OS and DFS in hepatocellular carcinoma and in Epstein–Barr-virus-positive and MLH1-defective gastric cancer [ 34 , 35 ]. In head and neck squamous cell carcinoma, LAG-3 was upregulated on tumor-infiltrating T cells and correlated with reduced OS [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

LAG-3-Expressing Tumor-Infiltrating T Cells Are Associated with Reduced Disease-Free Survival in Pancreatic Cancer

Seifert

Plesca

Müller

et al. 2021

Cancers

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T cells are the predominant immune cell population in the pancreatic tumor microenvironment. High CD8+ and Th1-polarized CD4+ T cell infiltration is associated with prolonged survival in human pancreatic ductal adenocarcinoma (PDAC). However, the expression pattern of co-stimulatory and inhibitory receptors by PDAC-infiltrating T cells and their prognostic significance are not well defined. In this study, we employed multiplex immunofluorescence to investigate the intratumoral expression of the co-stimulatory receptor inducible T-cell co-stimulator (ICOS), the inhibitory receptors lymphocyte-activation gene 3 (LAG-3), programmed death 1 (PD-1), and V-domain immunoglobulin suppressor of T cell activation (VISTA) by tumor-infiltrating T cells (CD3) in a cohort of 69 patients with resected PDAC. T cells were enriched particularly within the stromal area and were highly heterogeneous across tumors. Further, T cells were associated with prolonged disease-free survival (DFS). However, LAG-3 expression by PDAC-infiltrating T cells was correlated with reduced DFS. Our study highlights the biological importance of LAG-3 expression by tumor-infiltrating T cells. LAG-3+ T cells may represent a novel prognostic marker and a particularly attractive target for immunotherapeutic strategies in PDAC.

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Section: Discussionmentioning

confidence: 99%

LAG-3-Expressing Tumor-Infiltrating T Cells Are Associated with Reduced Disease-Free Survival in Pancreatic Cancer

Seifert

Plesca

Müller

et al. 2021

Cancers

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“…Consequently, the presence of LAG-3 on tumor-infiltrating immune cells has been described to be associated with poor prognosis and tumor progression. Individual studies reported this observation for various tumor types, including renal cell carcinoma [ 68 ], gastric cancer [ 69 ], bladder cancer [ 70 ], colorectal cancer [ 71 ], chronic lymphocytic leukemia [ 72 ], acute myeloid leukemia [ 73 ], follicular lymphoma [ 74 ], hepatocellular carcinoma [ 75 , 76 ], NSCLC [ 58 ], head and neck squamous cell carcinoma [ 77 ], esophageal squamous cell carcinoma [ 78 ], and diffuse large B cell lymphoma [ 79 ]. These studies suggested a contribution of LAG-3 to immune escape by the tumor, similarly to PD-1.…”

Section: The Prognostic Value Of Lag3mentioning

confidence: 99%

The Next-Generation Immune Checkpoint LAG-3 and Its Therapeutic Potential in Oncology: Third Time’s a Charm

Lecocq

Keyaerts

Devoogdt

et al. 2020

IJMS

102

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The blockade of immune checkpoints (ICPs), such as cytotoxic T lymphocyte associated protein-4 (CTLA-4) and programmed death-1 (PD-1) and its ligand (PD-L1), has propelled the field of immuno-oncology into its current era. Drugs targeting these ICPs have improved clinical outcome in a number of patients with solid and hematological cancers. Nonetheless, some patients have no benefit from these ICP-blocking therapies. This observation has instigated research into alternative pathways that are responsible for the escape of cancer cells from anti-cancer immune responses. From this research, a number of molecules have emerged as promising therapeutic targets, including lymphocyte activating gene-3 (LAG-3), a next-generation ICP. We will review the current knowledge on the biological activity of LAG-3 and linked herewith its expression on activated immune cells. Moreover, we will discuss the prognostic value of LAG-3 and how LAG-3 expression in tumors can be monitored, which is an aspect that is of utmost importance, as the blockade of LAG-3 is actively pursued in clinical trials.

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“…Whilst DNAM-1 showed the opposite effect on eDAEs depending on its expression on T or NK cells, we analyzed the differences between DNAM-1 + cells of each population. On T lymphocytes, DNAM-1 + cells had higher expression of PD-1, CD39, CD127, and LAG-3; immune exhaustion markers previously associated with poor HCC outcome [ 38 , 39 , 40 ]; and higher CD69, a cytotoxicity marker. On the other hand, NK DNAM-1 + cells expressed more CD16, an antigen-dependent cytotoxicity receptor with anti-tumor effect in HCC [ 41 ], and less LAG-3 and CD39.…”

Section: Discussionmentioning

confidence: 94%

Activated Lymphocytes and Increased Risk of Dermatologic Adverse Events during Sorafenib Therapy for Hepatocellular Carcinoma

Corominas

Sapena

Sanduzzi‐Zamparelli

et al. 2021

Cancers

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Advanced hepatocellular carcinoma patients treated with sorafenib who develop early dermatologic adverse events (eDAEs) have a better prognosis. This may be linked to immune mechanisms, and thus, it is relevant to assess the association between peripheral immunity and the probability of developing eDAEs. Peripheral blood mononuclear cells of 52 HCC patients treated with sorafenib were analyzed at baseline and throughout the first eight weeks of therapy. T, B, Natural Killer cells, and their immune checkpoints expression data were characterized by flow cytometry. Cytokine release and immune-suppression assays were carried out ex vivo. Cox baseline and time-dependent regression models were applied to evaluate the probability of increased risk of eDAEs. DNAM-1, PD-1, CD69, and LAG-3 in T cells, plus CD16 and LAG-3 in NK cells, are significantly associated with the probability of developing eDAEs. While NK DNAM-1+ cells express activation markers, T DNAM-1+ cells induce immune suppression and show immune exhaustion. This is the first study to report an association between immune checkpoints expression in circulating immune cells and the increased incidence of eDAEs. Our results support the hypothesis for an off-target role of sorafenib in immune modulation. We also describe a novel association between DNAM-1 and immune exhaustion in T cells.

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Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using multiplex quantitative analysis

Cited by 104 publications

References 53 publications

LAG-3-Expressing Tumor-Infiltrating T Cells Are Associated with Reduced Disease-Free Survival in Pancreatic Cancer

LAG-3-Expressing Tumor-Infiltrating T Cells Are Associated with Reduced Disease-Free Survival in Pancreatic Cancer

The Next-Generation Immune Checkpoint LAG-3 and Its Therapeutic Potential in Oncology: Third Time’s a Charm

Activated Lymphocytes and Increased Risk of Dermatologic Adverse Events during Sorafenib Therapy for Hepatocellular Carcinoma

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