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

2020 ◽  
Vol 21 (22) ◽  
pp. 8678
Author(s):  
Jiji V. D. Attia ◽  
Charlotte E. Dessens ◽  
Ricky van de Water ◽  
Ruben D. Houvast ◽  
Peter J. K. Kuppen ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Promote Tumor Growth ◽  
Peptide Binding Groove ◽  
Binding Groove ◽  
Human Leukocyte Antigen G

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.

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

2021 ◽  
Vol 12 ◽  
Author(s):  
Aifen Lin ◽  
Wei-Hua Yan
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Human Leukocyte ◽  
Solid Cancer ◽  
Biological Functions ◽  
Leukocyte Antigen ◽  
Promote Tumor Growth ◽  
Clinical Benefits ◽  
Human Leukocyte Antigen G

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.

scholarly journals Dual, HLA-B27 Subtype-dependent Conformation of a Self-peptide

2004 ◽  
Vol 199 (2) ◽  
pp. 271-281 ◽  
Author(s):  
Martin Hülsmeyer ◽  
Maria Teresa Fiorillo ◽  
Francesca Bettosini ◽  
Rosa Sorrentino ◽  
Wolfram Saenger ◽  
...  
Keyword(s):  
T Cell ◽  
Human Leukocyte ◽  
Salt Bridge ◽  
Binding Mode ◽  
Histocompatibility Antigens ◽  
Leukocyte Antigen ◽  
Cell Responses ◽  
Peptide Binding Groove ◽  
Major Histocompatibility Antigens ◽  
Binding Groove

The products of the human leukocyte antigen subtypes HLA-B*2705 and HLA-B*2709 differ only in residue 116 (Asp vs. His) within the peptide binding groove but are differentially associated with the autoimmune disease ankylosing spondylitis (AS); HLA-B*2705 occurs in AS-patients, whereas HLA-B*2709 does not. The subtypes also generate differential T cell repertoires as exemplified by distinct T cell responses against the self-peptide pVIPR (RRKWRRWHL). The crystal structures described here show that pVIPR binds in an unprecedented dual conformation only to HLA-B*2705 molecules. In one binding mode, peptide pArg5 forms a salt bridge to Asp116, connected with drastically different interactions between peptide and heavy chain, contrasting with the second, conventional conformation, which is exclusively found in the case of B*2709. These subtype-dependent differences in pVIPR binding link the emergence of dissimilar T cell repertoires in individuals with HLA-B*2705 or HLA-B*2709 to the buried Asp116/His116 polymorphism and provide novel insights into peptide presentation by major histocompatibility antigens.

scholarly journals HLA-G: A New Immune Checkpoint in Cancer?

2020 ◽  
Vol 21 (12) ◽  
pp. 4528
Author(s):  
Daniëlle Krijgsman ◽  
Jessica Roelands ◽  
Wouter Hendrickx ◽  
Davide Bedognetti ◽  
Peter J. K. Kuppen
Keyword(s):  
Immune Evasion ◽  
Immune Checkpoint ◽  
Expression Patterns ◽  
Tumor Development ◽  
Human Leukocyte ◽  
Immune Checkpoint Blockade ◽  
Leukocyte Antigen ◽  
Central Protein ◽  
Tumor Expression ◽  
Human Leukocyte Antigen G

Human leukocyte antigen G (HLA-G), known as a central protein in providing immune tolerance to the fetus in pregnant women, is also studied for a possible role in tumor development. Many studies have claimed HLA-G as a new immune checkpoint in cancer. Therefore, HLA-G and its receptors might be targets for immune checkpoint blockade in cancer immunotherapy. In order to substantiate that HLA-G is indeed an immune checkpoint in cancer, two important questions need to be answered: (1) To what extent is HLA-G expressed in the tumor by cancer cells? and (2) What is the function of HLA-G in cancer immune evasion? In this review, we discuss these questions. We agree that HLA-G is a potentially new immune checkpoint in cancer, but additional evidence is required to show the extent of intra-tumor and inter-tumor expression. These studies should focus on tumor expression patterns of the seven different HLA-G isoforms and of the receptors for HLA-G. Furthermore, specific roles for the different HLA-G isoforms should be established.

scholarly journals Unravelling the Proteomics of HLA-B*57:01+ Antigen Presenting Cells during Abacavir Medication

2022 ◽  
Vol 12 (1) ◽  
pp. 40
Author(s):  
Funmilola Josephine Haukamp ◽  
Eline Gall ◽  
Gia-Gia Toni Hò ◽  
Wiebke Hiemisch ◽  
Florian Stieglitz ◽  
...  
Keyword(s):  
T Cell ◽  
Human Leukocyte ◽  
Antigen Presenting Cells ◽  
Type B ◽  
Leukocyte Antigen ◽  
Hiv Therapy ◽  
Cell Mediated Immune Response ◽  
Peptide Binding Groove ◽  
Binding Groove ◽  
Antigen Presenting

Type B adverse drug reactions (ADRs) are unpredictable based on the drug’s pharmacology and represent a key challenge in pharmacovigilance. For human leukocyte antigen (HLA)-mediated type B ADRs, it is assumed that the protein/small-molecule interaction alters the biophysical and mechanistic properties of the antigen presenting cells. Sophisticated methods enabled the molecular appreciation of HLA-mediated ADRs; in several instances, the drug molecule occupies part of the HLA peptide binding groove and modifies the recruited peptide repertoire thereby causing a strong T-cell-mediated immune response that is resolved upon withdrawal of medication. The severe ADR in HLA-B*57:01+ patients treated with the antiretroviral drug abacavir (ABC) in anti-HIV therapy is an example of HLA-drug-T cell cooperation. However, the long-term damages of the HLA-B*57:01-expressing immune cells following ABC treatment remain unexplained. Utilizing full proteome sequencing following ABC treatment of HLA-B*57:01+ cells, we demonstrate stringent proteomic alteration of the HLA/drug presenting cells. The proteomic content indisputably reflects the cellular condition; this knowledge directs towards individual pharmacovigilance for the development of personalized and safe medication.

scholarly journals Structure of Human Histocompatibility Leukocyte Antigen (Hla)-Cw4, a Ligand for the Kir2d Natural Killer Cell Inhibitory Receptor

1999 ◽  
Vol 190 (1) ◽  
pp. 113-124 ◽  
Author(s):  
Qing R. Fan ◽  
Don C. Wiley
Keyword(s):  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Complex Molecule ◽  
Major Histocompatibility Complex Molecule ◽  
Inhibitory Receptor ◽  
Leukocyte Antigen ◽  
Consensus Peptide ◽  
Peptide Binding Groove ◽  
Binding Groove

The crystal structure of the human class I major histocompatibility complex molecule, human histocompatibility leukocyte antigen (HLA)-Cw4, the ligand for a natural killer (NK) cell inhibitory receptor, has been determined, complexed with a nonameric consensus peptide (QYDDAVYKL). Relative to HLA-A2, the peptide binding groove is widened around the COOH terminus of the α1 helix, which contains residues that determine the specificity of HLA-Cw4 for the inhibitory NK receptor, KIR2D. The structure reveals an unusual pattern of internal hydrogen bonding among peptide residues. The peptide is anchored in four specificity pockets in the cleft and secured by extensive hydrogen bonds between the peptide main chain and the cleft. The surface of HLA-Cw4 has electrostatic complementarity to the surface of the NK cell inhibitory receptor KIR2D.

Primary cutaneous CD8+ and CD56+ T-cell lymphomas express HLA-G and killer-cell inhibitory ligand, ILT2

Blood ◽  
2004 ◽  
Vol 103 (5) ◽  
pp. 1796-1798 ◽  
Author(s):  
Mirjana Urosevic ◽  
Jivko Kamarashev ◽  
Günter Burg ◽  
Reinhard Dummer
Keyword(s):  
T Cell ◽  
Clinical Course ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Interleukin 10 ◽  
Leukocyte Antigen ◽  
T Cell Lymphomas ◽  
Cutaneous Lymphomas ◽  
Aggressive Clinical Course ◽  
Human Leukocyte Antigen G

Abstract Primary cutaneous lymphomas constitute a spectrum of diseases characterized by a clonal accumulation of lymphocytes in the skin. Cutaneous T-cell lymphomas of the cytotoxic phenotype, including CD8+ and CD56+ lymphomas, are rare entities that have only been recently recognized and characterized. These lymphomas often show an aggressive clinical course. We investigated the expression of human leukocyte antigen G (HLA-G) and interleukin 10 (IL-10) in conjunction with expression of HLA-G killer-cell inhibitory receptor ligand immunoglobulin-like transcript 2 (ILT2) in 3 CD56+CD4+ and 4 CD8+ cutaneous T-cell lymphomas. HLA-G expression was detected in 2 of 3 lymphomas of the CD56+CD4+ type and in all lymphomas of CD8+ type. It is of note that CD56+CD4+ lymphomas displayed stronger HLA-G reactivity. The expression of IL-10 matched the expression of HLA-G. Together with the expression of IL-10, HLA-G might be one of the factors accounting for the evasion of immunosurveillance, thus contributing to aggressive phenotype of these lymphoma entities.

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