Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
7.8
5.6
Journals
IJMS
Special Issues
HLA-G: A New Target for Immune Checkpoint Inhibitors in Cancer?
ijms-logo
Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

► Journal Menu

Journal Browser

► Journal Browser
share announcement

HLA-G: A New Target for Immune Checkpoint Inhibitors in Cancer?

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 27738

Special Issue Editor

Dr. Peter J. K. Kuppen

E-Mail Website
Guest Editor
Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
Interests: colorectal cancer; tumor-immmune interactions; cancer genetics and epigenetics; immunotherapy; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Human leukocyte antigen G (HLA-G) has already been known for a long time as a central protein for providing immune tolerance to the fetus in pregnant women. Because of its immune-inhibiting function, it is also studied for its potential role in cancer. Over the years, many studies have reported on the expression of HLA-G in many different types of cancers, usually via an evaluation of the immunohistochemical (IHC) staining’s of tumor tissues using HLA-G recognizing antibodies. These studies showed that many tumors are IHC-positive for HLA-G expression, and most studies showed this is associated with poor clinical outcomes in cancer patients. Although IHC is a widely accepted technique, the detection of HLA-G with IHC is still controversial. This is, among other reasons, because of the use of different antibodies that recognize different HLA-G epitopes/isoforms and that are known for cross reactivity, resulting in reported HLA-G tumor expression levels that vary widely. Despite these variations, the results suggest that HLA-G can be expressed de novo by human malignant cells, contributing to tumor escape from the hosts’ immune surveillance. Therefore, HLA-G is a new potential target for immune checkpoint inhibitors in cancer immunotherapy. In this Special Issue on HLA-G in cancer, we focus on evidence that HLA-G is indeed expressed by different types of tumors. Furthermore, we focus on why tumor cells express HLA-G; what genetic or epigenetic mechanisms are behind it and what is the contribution of the 7 known HLA-G isoforms. Finally, we focus on evidence that HLA-G functions as an immune checkpoint in cancer.  This in the context of HLA-G receptors, like LILRB1/ILT2 and LILRB2/ILT4. The aim is to finally conclude if, and what kind of inhibitors should be developed for therapeutical purposes to block HLA-G-mediated immune interactions in cancer.

Prof. Peter Kuppen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer
  • HLA-G
  • immunoediting
  • immune checkpoint inhibitors
  • clinical outcome
  • immunotherapy
  • HLA-G receptor
  • LILRB1/ILT2
  • LILRB2/ILT4

Published Papers (5 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review

11 pages, 1328 KiB  
Editorial
HLA-G: A New Immune Checkpoint in Cancer?
by Daniëlle Krijgsman, Jessica Roelands, Wouter Hendrickx, Davide Bedognetti and Peter J. K. Kuppen
Int. J. Mol. Sci. 2020, 21(12), 4528; https://doi.org/10.3390/ijms21124528 - 25 Jun 2020
Cited by 53 | Viewed by 7439
Abstract
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, [...] Read more.
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. Full article
(This article belongs to the Special Issue HLA-G: A New Target for Immune Checkpoint Inhibitors in Cancer?)
►▼ Show Figures

Figure 1

Research

Jump to: Editorial, Review

23 pages, 3899 KiB  
Article
Characterization of HLA-G Regulation and HLA Expression in Breast Cancer and Malignant Melanoma Cell Lines upon IFN-γ Stimulation and Inhibition of DNA Methylation
by Nanna Jørgensen, Abid Sayed, Helene Bjerregaard Jeppesen, Gry Persson, Iben Weisdorf, Tina Funck and Thomas Vauvert Faurschou Hviid
Int. J. Mol. Sci. 2020, 21(12), 4307; https://doi.org/10.3390/ijms21124307 - 17 Jun 2020
Cited by 10 | Viewed by 4169
Abstract
The potential role of human leukocyte antigen (HLA)-G as a target for new cancer immunotherapy drugs has increased the interest in the analysis of mechanisms by which HLA-G expression is regulated, and how the expression can be manipulated. We characterized HLA expression in [...] Read more.
The potential role of human leukocyte antigen (HLA)-G as a target for new cancer immunotherapy drugs has increased the interest in the analysis of mechanisms by which HLA-G expression is regulated, and how the expression can be manipulated. We characterized HLA expression in breast cancer and malignant melanoma cell lines and investigated the induction of HLA-G expression by two distinct mechanisms: stimulation with interferon (IFN)-γ or inhibition of methylation by treatment with 5-aza-2’-deoxycytidine (5-aza-dC). The effect of IFN-γ and 5-aza-dC on HLA expression was dependent on the cancer cell lines studied. However, in general, surface expression of HLA class Ia was induced on all cell lines. Surface expression of HLA-G was inconclusive but induction of HLA-G mRNA was prevalent upon treatment with 5-aza-dC and a combination of IFN-γ and 5-aza-dC. IFN-γ alone failed to induce HLA-G expression in the HLA-G-negative cell lines. The results support that HLA-G expression is regulated partly by DNA methylation. Furthermore, IFN-γ may play a role in the maintenance of HLA-G expression rather than inducing expression. The study demonstrates the feasibility of manipulating HLA expression and contributes to the exploration of mechanisms that can be potential targets for immunotherapy in breast cancer and malignant melanoma. Full article
(This article belongs to the Special Issue HLA-G: A New Target for Immune Checkpoint Inhibitors in Cancer?)
►▼ Show Figures

Figure 1

12 pages, 4103 KiB  
Article
A Unique Regulation Region in the 3′ UTR of HLA-G with a Promising Potential
by Adi Reches, Orit Berhani and Ofer Mandelboim
Int. J. Mol. Sci. 2020, 21(3), 900; https://doi.org/10.3390/ijms21030900 - 30 Jan 2020
Cited by 11 | Viewed by 3615
Abstract
Human leukocyte antigen G (HLA-G) is a non-classical human leukocyte antigen (HLA) class I protein that interacts with inhibitory receptors and is commonly overexpressed in various cancers, thereby establishing itself as an inhibitory checkpoint immune ligand. It is also expressed in trophoblast cells [...] Read more.
Human leukocyte antigen G (HLA-G) is a non-classical human leukocyte antigen (HLA) class I protein that interacts with inhibitory receptors and is commonly overexpressed in various cancers, thereby establishing itself as an inhibitory checkpoint immune ligand. It is also expressed in trophoblast cells during pregnancy and protects the fetus from immune rejection. Despite its crucial role and its intriguing expression pattern, the regulation of HLA-G’s expression is only partially understood. HLA-G’s mRNA is expressed in many tissues but the protein expression is restricted only to the cells mentioned above. Therefore, we suggest that HLA-G is post-transcriptionally regulated. Here, we reveal a distinctive site present only in the 3′ Untranslated region (UTR) of HLA-G, which might explain its unique expression pattern. Consequently, we attempted to find binding factors such as RNA binding proteins (RBPs) and microRNAS (miRs) that regulate HLA-G expression by interacting with this distinct site present in its 3′ UTR. Our research indicates that this site should be further studied in order to reveal its significance. Full article
(This article belongs to the Special Issue HLA-G: A New Target for Immune Checkpoint Inhibitors in Cancer?)
►▼ Show Figures

Figure 1

11 pages, 1742 KiB  
Article
Evaluation of the Reactivity and Receptor Competition of HLA-G Isoforms toward Available Antibodies: Implications of Structural Characteristics of HLA-G Isoforms
by Atsushi Furukawa, Manami Meguro, Rika Yamazaki, Hiroshi Watanabe, Ami Takahashi, Kimiko Kuroki and Katsumi Maenaka
Int. J. Mol. Sci. 2019, 20(23), 5947; https://doi.org/10.3390/ijms20235947 - 26 Nov 2019
Cited by 10 | Viewed by 4939
Abstract
The human leucocyte antigen (HLA)-G, which consists of seven splice variants, is a tolerogenic immune checkpoint molecule. It plays an important role in the protection of the fetus from the maternal immune response by binding to inhibitory receptors, including leukocyte Ig-like receptors (LILRs). [...] Read more.
The human leucocyte antigen (HLA)-G, which consists of seven splice variants, is a tolerogenic immune checkpoint molecule. It plays an important role in the protection of the fetus from the maternal immune response by binding to inhibitory receptors, including leukocyte Ig-like receptors (LILRs). Recent studies have also revealed that HLA-G is involved in the progression of cancer cells and the protection from autoimmune diseases. In contrast to its well characterized isoform, HLA-G1, the binding activities of other major HLA-G isoforms, such as HLA-G2, toward available anti-HLA-G antibodies are only partially understood. Here, we investigate the binding specificities of anti-HLA-G antibodies by using surface plasmon resonance. MEM-G9 and G233 showed strong affinities to HLA-G1, with a nM range for their dissociation constants, but did not show affinities to HLA-G2. The disulfide-linker HLA-G1 dimer further exhibited significant avidity effects. On the other hand, 4H84 and MEM-G1, which can be used for the Western blotting of HLA-G isoforms, can bind to native HLA-G2, while MEM-G9 and G233 cannot. These results reveal that HLA-G2 has a partially intrinsically disordered structure. Furthermore, MEM-G1, but not 4H84, competes with the LILRB2 binding of HLA-G2. These results provide novel insight into the functional characterization of HLA-G isoforms and their detection systems. Full article
(This article belongs to the Special Issue HLA-G: A New Target for Immune Checkpoint Inhibitors in Cancer?)
►▼ Show Figures

Figure 1

Review

Jump to: Editorial, Research

18 pages, 12743 KiB  
Review
The Molecular and Functional Characteristics of HLA-G and the Interaction with Its Receptors: Where to Intervene for Cancer Immunotherapy?
by Jiji V. D. Attia, Charlotte E. Dessens, Ricky van de Water, Ruben D. Houvast, Peter J. K. Kuppen and Daniëlle Krijgsman
Int. J. Mol. Sci. 2020, 21(22), 8678; https://doi.org/10.3390/ijms21228678 - 17 Nov 2020
Cited by 32 | Viewed by 6170
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue HLA-G: A New Target for Immune Checkpoint Inhibitors in Cancer?)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-5
Back to TopTop