Evaluation of the Reactivity and Receptor Competition of HLA-G Isoforms toward Available Antibodies: Implications of Structural Characteristics of HLA-G Isoforms

Furukawa, Akinori; Meguro, Manami; Yamazaki, Rika; Watanabe, Hiroshi; Takahashi, Ami; Kuroki, Kazuhiko; Maenaka, Katsumi

doi:10.3390/ijms20235947

Cited by 11 publications

(12 citation statements)

References 43 publications

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“…This finding is in line with the previous study on CRC showing 5%–28% of cells positive with the MEM/G‐1 antibody 16 . The MEM‐G1 antibody recognizes the denatured form of the HLA‐G heavy chain, all isoforms, 14,21 and the native HLA‐G2 22 . The observed pattern of HLA‐G expression in this study supported the overall low expression of HLA‐G in up to 70% of CRC tumors and lack of association between the positive staining and prognosis 12 .…”

Section: Figuresupporting

confidence: 92%

HLA‐G expression correlates with histological grade but not with prognosis in colorectal carcinoma

Kaprio

Sariola

Linder

et al. 2021

HLA

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Trophoblast‐specific expression of HLA‐G induces immune tolerance for the developing fetus. Pathological HLA‐G expression later in life might contribute to immune escape of various cancers. We studied the still controversial role of HLA‐G in colorectal carcinoma (CRC) using the MEM‐G/1 antibody and a tissue microarray series of CRC tumors (n = 317). HLA‐G expression appeared in 20% of the tumors and showed high intratumoral heterogeneity. HLA‐G positivity was associated with better differentiation (p = 0.002) and non‐mucinous histology (p = 0.008). However, HLA‐G expression alone showed no prognostic value: 5‐years disease‐specific survival among patients with HLA‐G expression was 68.9% (95% CI: 62.7%–75.0%) compared to 74.8% (95% CI: 63.2%–86.3%) among those without expression. These results support a modulatory role of HLA‐G in CRC.

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Section: Figuresupporting

confidence: 92%

HLA‐G expression correlates with histological grade but not with prognosis in colorectal carcinoma

Kaprio

Sariola

Linder

et al. 2021

HLA

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“…Therefore, a cocktail of different antibodies that individually target each receptor may be necessary in order to block the interaction of HLA-G with all its receptors. Direct blockade of HLA-G2 homodimers has been demonstrated for MEM-G/1, which blocks the binding site of HLA-G2 for ILT4, thereby preventing binding [ 19 ]. In contrast, MEM-G/9 and G233 bind to HLA-G1, but do not share the same binding site of ILT2 [ 19 ].…”

Section: Hla-g As Target For Immune Checkpoint Inhibition In Cancementioning

confidence: 99%

“…Direct blockade of HLA-G2 homodimers has been demonstrated for MEM-G/1, which blocks the binding site of HLA-G2 for ILT4, thereby preventing binding [ 19 ]. In contrast, MEM-G/9 and G233 bind to HLA-G1, but do not share the same binding site of ILT2 [ 19 ]. Whether these antibodies can prevent the binding, either directly or indirectly, needs to be explored further.…”

Section: Hla-g As Target For Immune Checkpoint Inhibition In Cancementioning

confidence: 99%

“…Additionally, cross-reaction has been reported of widely used HLA-G-recognizing antibodies with proteins other than HLA-G, such as classical HLA class I antigens [ 17 , 18 ]. Moreover, it is unsure if the existing antibodies can block the interaction between HLA-G and its receptors since the majority of the antibodies do not share the same binding site as HLA-G receptors [ 19 ]. Consequently, the existing monoclonal antibodies directed against HLA-G are not suitable for immune checkpoint inhibition in a clinical setting [ 17 , 18 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

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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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“…Noteworthy, because MEM-G/1 targets an extracellular domain of native HLA-G which might be partially intrinsically disordered, this antibody not only can detect native forms of HLA-G2, but also competes with the LILRB2 binding of HLA-G2. These results provide novel insight into the functional characterization of HLA-G isoforms, pointing out its potential as ICP inhibitor (173). 87G, MEM-G/9 and G233 mAbs bind to conformational HLA-G α1 domain associated to the β2M (HLA-G1 and HLA-G5).…”

Section: Discussionmentioning

confidence: 86%

HLA-G Neo-Expression on Tumors

et al. 2020

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HLA-G is known to modulate the immune system activity in tissues where physiological immune-tolerance is necessary (i.e., maternal-fetal interface, thymus, and cornea). However, the frequent neo-expression of HLA-G in many cancer types has been previously and extensively described and is correlated with a bad prognosis. Despite being an MHC class I molecule, HLA-G is highly present in tumor context and shows unique characteristics of tissue restriction of a Tumor Associated Antigen (TAA), and potent immunosuppressive activity of an Immune CheckPoint (ICP). Consequently, HLA-G appears to be an excellent molecular target for immunotherapy. Although the relevance of HLA-G in cancer incidence and development has been proven in numerous tumors, its neo-expression pattern is still difficult to determine. Indeed, the estimation of HLA-G's actual expression in tumor tissue is limited, particularly concerning the presence and percentage of the new non-canonical isoforms, for which detection antibodies are scarce or inexistent. Here, we summarize the current knowledge about HLA-G neo-expression and implication in various tumor types, pointing out the need for the development of new tools to analyze in-depth the HLA-G neo-expression patterns, opening the way for the generation of new monoclonal antibodies and cell-based immunotherapies.

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Evaluation of the Reactivity and Receptor Competition of HLA-G Isoforms toward Available Antibodies: Implications of Structural Characteristics of HLA-G Isoforms

Cited by 11 publications

References 43 publications

HLA‐G expression correlates with histological grade but not with prognosis in colorectal carcinoma

HLA‐G expression correlates with histological grade but not with prognosis in colorectal carcinoma

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

HLA-G Neo-Expression on Tumors

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