Genetic signature of CTLA-4, BTLA, TIM-3 and LAG-3 molecular expression in colorectal cancer patients: Implications in diagnosis and survival outcomes

Kamal, Amany M.; Wasfey, Eman F.; Elghamry, W.R.; Sabry, Omar M.; Elghobary, Hany; Radwan, Sara M.

doi:10.1016/j.clinbiochem.2021.06.007

Cited by 27 publications

(16 citation statements)

References 34 publications

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“…Lately, the up-regulation of BTLA expression has been linked to tumor progression, with the worst prognosis reported for human melanoma [20], chronic and small lymphocytic leukemias [21], colorectal cancer patients [22], as well as gastric adenocarcinoma [23]. Those results come in accordance with the findings of this study, as the up-regulated BTLA expression was correlated with a decrease in the overall survival of AML patients, suggesting its potential use as a prognostic marker.…”

Section: Discussionsupporting

confidence: 91%

The prospective prognostic value of the immune checkpoint BTLA expression in adult acute myeloid leukemia patients

Radwan

Elleboudy

Nabih

et al. 2021

Egypt J Med Hum Genet

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Background One of the crucial functions of the immune system is to prevent tumorigenesis, yet cancer occurs when malignant cells manage to evade immune surveillance via multiple strategies. Accordingly, this study aimed at assessing the potential significance of the novel immune checkpoint B and T lymphocyte attenuator (BTLA) as a prognostic marker in acute myeloid leukemia (AML), in addition to how it relates to response to treatment and patients’ survival. Thus, mRNA expression of BTLA was investigated on peripheral blood in 60 AML patients and 15 healthy controls. Results BTLA expression was found to be significantly elevated (p = 0.024) in the tested AML cases in comparison with healthy controls. Moreover, BTLA was over-expressed in the CD13, CD33, and HLA-DR positive cases as compared to their negative counterparts (p = 0.003; p < 0.001, and p = 0.001, respectively), and cases showing BTLA over-expression had significantly poorer overall survival times (p = 0.001) as confirmed by Kaplan–Meier survival analysis. Conclusion These observations suggest that BTLA over-expression may be associated with reduced immunity against tumors and could be recommended as a promising biomarker for unfavorable prognosis in AML.

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Section: Discussionsupporting

confidence: 91%

The prospective prognostic value of the immune checkpoint BTLA expression in adult acute myeloid leukemia patients

Radwan

Elleboudy

Nabih

et al. 2021

Egypt J Med Hum Genet

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“…In hepatocellular carcinoma (HCC), higher densities of LAG-3 + cells were associated with shorter OS and disease-free survival (DFS) ( 106 ). Consistent with this result, LAG-3 expression was negatively correlated with OS in colorectal cancer ( 107 ). In patients diagnosed with locally advanced esophageal adenocarcinoma, the complete pathological response (CR), LAG-3 and CXCL9 were more predictive than CR alone in terms of DFS, which is correlated with the reduced rate of recurrence ( 108 ).…”

Section: Preclinical Data In Esophageal Cancersupporting

confidence: 71%

Novel Immune Checkpoints in Esophageal Cancer: From Biomarkers to Therapeutic Targets

et al. 2022

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Esophageal cancer ranks as the sixth most common cause of cancer death worldwide. Due to the limited efficacy of conventional therapeutic strategies, including surgery, chemotherapy, and radiotherapy, treatments are still far from satisfactory in terms of survival, prompting the search for novel treatment methods. Immune checkpoints play crucial roles in immune evasion mediated by tumor cells, and successful clinical outcomes have been achieved via blocking these pathways. However, only a small fraction of patients can benefit from current immune checkpoint inhibitors targeting programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated protein-4. Unfortunately, some patients show primary and/or acquired resistance to immune checkpoint inhibitors. Until now, novel immune checkpoint pathways have rarely been studied in esophageal cancer, and there is a great need for biomarkers to predict who will benefit from existing strategies. Herein, we primarily discuss the roles of new immune checkpoints as predictive biomarkers and therapeutic targets for esophageal cancer. In addition, we summarize the ongoing clinical trials and provide future research directions targeting these pathways.

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“…The LAG3 expression level can be a marker of poor prognosis in various tumors. In NSCLC and advanced CRC, the high expression of FGL1 and LAG3 are related to the poor 5-year OS, respectively ( 43 , 85 ), high level of soluble LAG3(>377pg/ml) predicts unfavorable PFS and OS in HNSCC ( 86 ). More LAG3 + cells induce the immunosuppressive microenvironment and predict the poor prognosis, in EBV-positive and MLH1-defective gastric cancer, high infiltration of LAG3 + cells may induce immune escape in tumors with fewer IFN-γ + cells and perforin-1 + cells and more Treg cells and M2 macrophages in this subtype of gastric cancer ( 87 ), similar results can be found in MIBC and pancreatic ductal adenocarcinoma ( 56 , 88 ).…”

Section: Clinical Application Of Lag3/fglmentioning

confidence: 99%

Immune Checkpoint LAG3 and Its Ligand FGL1 in Cancer

et al. 2022

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LAG3 is the most promising immune checkpoint next to PD-1 and CTLA-4. High LAG3 and FGL1 expression boosts tumor growth by inhibiting the immune microenvironment. This review comprises four sections presenting the structure/expression, interaction, biological effects, and clinical application of LAG3/FGL1. D1 and D2 of LAG3 and FD of FGL1 are the LAG3-FGL1 interaction domains. LAG3 accumulates on the surface of lymphocytes in various tumors, but is also found in the cytoplasm in non-small cell lung cancer (NSCLC) cells. FGL1 is found in the cytoplasm in NSCLC cells and on the surface of breast cancer cells. The LAG3-FGL1 interaction mechanism remains unclear, and the intracellular signals require elucidation. LAG3/FGL1 activity is associated with immune cell infiltration, proliferation, and secretion. Cytokine production is enhanced when LAG3/FGL1 are co-expressed with PD-1. IMP321 and relatlimab are promising monoclonal antibodies targeting LAG3 in melanoma. The clinical use of anti-FGL1 antibodies has not been reported. Finally, high FGL1 and LAG3 expression induces EGFR-TKI and gefitinib resistance, and anti-PD-1 therapy resistance, respectively. We present a comprehensive overview of the role of LAG3/FGL1 in cancer, suggesting novel anti-tumor therapy strategies.

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Genetic signature of CTLA-4, BTLA, TIM-3 and LAG-3 molecular expression in colorectal cancer patients: Implications in diagnosis and survival outcomes

Cited by 27 publications

References 34 publications

The prospective prognostic value of the immune checkpoint BTLA expression in adult acute myeloid leukemia patients

The prospective prognostic value of the immune checkpoint BTLA expression in adult acute myeloid leukemia patients

Novel Immune Checkpoints in Esophageal Cancer: From Biomarkers to Therapeutic Targets

Immune Checkpoint LAG3 and Its Ligand FGL1 in Cancer

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