The Molecular and Functional Characteristics of HLA-G and the Interaction with Its Receptors: Where to Intervene for Cancer Immunotherapy?

Attia, Jiji V D; Dessens, Charlotte E; Water, Ricky van de; Houvast, Ruben D.; Kuppen, Peter J. K.; Krijgsman, Daniëlle

doi:10.3390/ijms21228678

Cited by 34 publications

(35 citation statements)

References 117 publications

(84 reference statements)

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“…Third, being the landscape of HLA-G isoform expression in tumor tissues can’t be specified, application of HLA-G/ILTs-targeted ICIs for cancer treatment can be aimless. Furthermore, HLA-G/ILTs engagement is isoform dependent, where HLA-G1 and HLA-G5 binds ILT-2, and HLA-G1, -G2, -G4, -G5, and HLA-G6 binds ILT-4 ( 118 ). Differential expression of HLA-G isoforms does exist in tumor cells whereas the underlying mechanisms are yet to be explored.…”

Section: Discussionmentioning

confidence: 99%

HLA-G/ILTs Targeted Solid Cancer Immunotherapy: Opportunities and Challenges

Lin

Yan

2021

Front. Immunol.

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Immune checkpoint inhibitors (ICIs) have become a promising immunotherapy for cancers. Human leukocyte antigen-G (HLA-G), a neoantigen, its biological functions and clinical relevance have been extensively investigated in malignancies, and early clinical trials with “anti-HLA-G strategy” are being launched for advance solid cancer immunotherapy. The mechanism of HLA-G as a new ICI is that HLA-G can bind immune cell bearing inhibitory receptors, the immunoglobulin-like transcript (ILT)-2 and ILT-4. HLA-G/ILT-2/-4 (HLA-G/ILTs) signaling can drive comprehensive immune suppression, promote tumor growth and disease progression. Though clinical benefits could be expected with application of HLA-G antibodies to blockade the HLA-G/ILTs signaling in solid cancer immunotherapy, major challenges with the diversity of HLA-G isoforms, HLA-G/ILTs binding specificity, intra- and inter-tumor heterogeneity of HLA-G, lack of isoform-specific antibodies and validated assay protocols, which could dramatically affect the clinical efficacy. Clinical benefits of HLA-G-targeted solid cancer immunotherapy may be fluctuated or even premature unless major challenges are addressed.

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Section: Discussionmentioning

confidence: 99%

HLA-G/ILTs Targeted Solid Cancer Immunotherapy: Opportunities and Challenges

Lin

Yan

2021

Front. Immunol.

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“…The immunosuppressive function of HLA-G is mediated by its interaction with immune inhibitory receptors, immunoglobulin-like transcript (ILT)-2 and/or ILT-4 ( 8 ). These receptors are expressed in tumor cells, as well as in a wide range of immune cells, such as B cells, T cells, natural killer cells (NK), dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs) ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

Prognostic Significance of Immune Checkpoints HLA-G/ILT-2/4 and PD-L1 in Colorectal Cancer

Chen

Han

et al. 2021

Front. Immunol.

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Immune checkpoint inhibitors (ICIs) have become a promising area of research for cancer treatment. In addition to the well-known ICIs targeting PD-1/PD-L1, HLA-G/ILT-2/-4 is relatively new immune checkpoint that has been evaluated in early clinical trials in patients with advanced solid tumors. In this study, the expression of HLA-G (n=157), ILT-2/4 (n=82), and PD-L1 (n=70) in epithelial cell adhesion molecule (EpCAM)-positive colorectal cancer (CRC) cells was analyzed by multicolor flow cytometry, and the prognostic significance of these molecules was evaluated. In EpCAM+ CRC cells, the median percentages of HLA-G, ILT-2, ILT-4, and PD-L1 were 14.90%, 67.70%, 8.55% and 80.30%, respectively. In addition, a positive correlation was observed between them (all p<0.001). Higher levels of these immune checkpoint proteins are associated with lymph node metastasis. In addition to the AJCC stage (p=0.001), Kaplan-Meier survival analysis showed that higher levels of HLA-G (p=0.041), ILT-2 (p=0.060), ILT-4 (p<0.001), PD-L1 (p=0.012), HLA-GILT4 (p<0.001) and ILT-2ILT-4 (p<0.001) were significantly associated with shorter survival of CRC patients. When CRC patients were stratified by early and advanced AJCC stages, HLA-G levels were only related to the survival among CRC patients with early disease stage (p=0.024), while ILT-4 levels were significant for both CRC patients with early (p=0.001) and advanced (p=0.020) disease stages. Multivariate cox regression analysis revealed that advanced AJCC stage (HR=2.435; p=0.005) and higher ILT-4 levels (HR=2.198; p=0.063) were independent risk factors for poor outcomes in patients with CRC. In summary, among the immune checkpoints, HLA-G/ILT-2/4 and PD-L1, ILT-4 is the most significant prognostic indicator of CRC. This finding indicated that a combination of immunotherapy strategies, such as ILT-4 blockade, could improve the clinical outcomes in patients with cancer. Moreover, multicolor flow cytometry can be employed as a reliable and efficient, alternative to immunohistochemistry, for evaluating the immune checkpoint proteins expressed in tumor lesions.

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“…Immune cell alterations such as dendritic cells and Th2 cells are important triggers of tumor immune infiltration and subsequent vascular invasion, and their activation also correlates with the patient's response to immune and biological vaccine therapy (Moreira et al, 2020;Patel et al, 2020;Zhao et al, 2020). HLA and CCR also affect various aspects of the body's immune system (Attia et al, 2020). HLA and CCR in progressive tumors are more likely to be continuously activated and maintain the complex tumor microenvironment (Pankratova et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Large-Scale Transcriptome Analysis Identified a Novel Cancer Driver Genes Signature for Predicting the Prognostic of Patients With Hepatocellular Carcinoma

Gao

et al. 2021

Front. Pharmacol.

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Background: Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality and heterogeneity. Genetic mutations caused by driver genes are important contributors to the formation of the tumor microenvironment. The purpose of this study is to discuss the expression of cancer driver genes in tumor tissues and their clinical value in predicting the prognosis of HCC.Methods: All data were sourced from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) public databases. Differentially expressed and prognostic genes were screened by the expression distribution of the cancer driver genes and their relationship with survival. Candidate genes were subjected to functional enrichment and transcription factor regulatory network. We further constructed a prognostic signature and analyzed the survival outcomes and immune status between different risk groups.Results: Most cancer driver genes are specifically expressed in cancer tissues. Driver genes may influence HCC progression through processes such as transcription, cell cycle, and T-cell receptor-related pathways. Patients in different risk groups had significant survival differences (p < 0.05), and risk scores showed high predictive efficacy (AUC>0.69). Besides, risk subgroups were also associated with multiple immune functions and immune cell content.Conclusion: We confirmed the critical role of cancer driver genes in mediating HCC progression and the immune microenvironment. Risk subgroups contribute to the assessment of prognostic value in different patients and explain the heterogeneity of HCC.

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The Molecular and Functional Characteristics of HLA-G and the Interaction with Its Receptors: Where to Intervene for Cancer Immunotherapy?

Cited by 34 publications

References 117 publications

HLA-G/ILTs Targeted Solid Cancer Immunotherapy: Opportunities and Challenges

HLA-G/ILTs Targeted Solid Cancer Immunotherapy: Opportunities and Challenges

Prognostic Significance of Immune Checkpoints HLA-G/ILT-2/4 and PD-L1 in Colorectal Cancer

Large-Scale Transcriptome Analysis Identified a Novel Cancer Driver Genes Signature for Predicting the Prognostic of Patients With Hepatocellular Carcinoma

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