HLA-G: A New Immune Checkpoint in Cancer?

Krijgsman, Daniëlle; Roelands, Jessica; Hendrickx, Wouter; Bedognetti, Davide; Kuppen, Peter J. K.

doi:10.3390/ijms21124528

Cited by 60 publications

(50 citation statements)

References 67 publications

(92 reference statements)

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“…These findings sharply compounded the clinical relevance of HLA-G in tumor patients ( 62 ). Second, being lack of international validated or recommended assay protocols, both performance and cut-off points are diverse and unconcordance in interpretation of HLA-G expression across studies is rather common ( 117 ). 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.…”

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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“…HLA-G1 and -G5 are the only isoforms that can bind the light chain β2M. Adapted from Krijgsman et al [ 33 ]. Abbreviations: β2-microglobulin (β2M), cytoplasmic domain (CD), exon (E), human leukocyte antigen G (HLA-G), signal peptide (SP), three prime untranslated region (3′UTR), transmembrane region (TR).…”

Section: Figurementioning

confidence: 99%

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

Attia

Dessens

Water

et al. 2020

IJMS

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Human leukocyte antigen G (HLA-G) mediates maternal-fetal immune tolerance. It is also considered an immune checkpoint in cancer since it may mediate immune evasion and thus promote tumor growth. HLA-G is, therefore, a potential target for immunotherapy. However, existing monoclonal antibodies directed against HLA-G lack sufficient specificity and are not suitable for immune checkpoint inhibition in a clinical setting. For this reason, it is essential that alternative approaches are explored to block the interaction between HLA-G and its receptors. In this review, we discuss the structure and peptide presentation of HLA-G, and its interaction with the receptors Ig-like transcript (ILT) 2, ILT4, and Killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4). Based on our findings, we propose three alternative strategies to block the interaction between HLA-G and its receptors in cancer immunotherapy: (1) prevention of HLA-G dimerization, (2) targeting the peptide-binding groove of HLA-G, and (3) targeting the HLA-G receptors. These strategies should be an important focus of future studies that aim to develop immune checkpoint inhibitors to block the interaction between HLA-G and its receptors for the treatment of cancer.

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“…However, no discrimination can currently be made between the different HLA-G isoforms in the tumour lesions when 4H84 (or any mAb that recognises all HLA-G isoforms for that matter) is used as HLA-G-detecting mAb. Therefore, until it becomes possible to make a distinction between the different HLA-G isoforms and determine the proportions wherein distinct HLA-G isoforms are presented within the tumour lesion, it remains uncertain what the exact role of specific HLA-G isoforms is in different tumour types [ 71 ]. A solution to these issues would be the development of mAbs that exclusively stain the distinct HLA-G isoforms, but that is challenging.…”

Section: Discussionmentioning

confidence: 99%

“…Other approaches to measure HLA-G in tumour lesions could include using HLA-G mRNA expression levels. However, it has been shown in CRC samples that HLA-G mRNA expression levels does not necessarily translate to HLA-G protein expression [ 71 , 72 ]. This is because HLA-G mRNA is under strict post-translational control by HLA-G mRNA-specific miRNA’s [ 63 , 73 , 74 , 75 ].…”

Section: Discussionmentioning

confidence: 99%

A Critical Assessment of the Association between HLA-G Expression by Carcinomas and Clinical Outcome

Water

Krijgsman

Houvast

et al. 2021

IJMS

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Human leukocyte antigen-G (HLA-G) conveys immunological tolerance at the maternal-foetal interface. HLA-G expression by tumour cells may also play such a role, resulting in tumour immune evasion, making HLA-G a potential target for immunotherapies. The aim of this review was to determine to what extent it is justified that HLA-G expression is considered as a target for immune checkpoint inhibiting therapy by critically assessing the association between HLA-G expression by carcinomas and clinical outcome of patients. The used HLA-G-detecting mAb, HLA-G quantification methods and statistically significant HLA-G-associated clinicopathological parameters are discussed. Tumour HLA-G expression correlated with poor clinical outcome in breast, esophageal, gastric and hepatocellular carcinoma patients. Tumour HLA-G expression was not associated with clinical outcome in ovarian and oral carcinoma patients. Cervical, colorectal, lung, and pancreatic carcinoma patients presented discrepant and therefore inconclusive results regarding the association between tumour HLA-G expression and clinical outcome. These disparities might partly be the result of differences in the methodological approach to quantify HLA-G expression between studies. Therefore, implementation of universal methodological procedures is strongly advised. Overall, HLA-G expression did not univocally result in poor clinical outcome of carcinoma patients. This implies that tumour HLA-G expression is not necessarily part of an inhibited tumour-immune response and tumour progression. Consequently, it remains elusive whether HLA-G expression by carcinomas functions as an immune checkpoint molecule affecting a tumour-immune response. It may also reflect derailed control of gene expression in tumours, with no real functional consequences.

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HLA-G: A New Immune Checkpoint in Cancer?

Cited by 60 publications

References 67 publications

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

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

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

A Critical Assessment of the Association between HLA-G Expression by Carcinomas and Clinical Outcome

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