HLA-G Expressing Immune Cells in Immune Mediated Diseases

Contini, Paola; Murdaca, Giuseppe; Puppo, Francesco; Negrini, Simone

doi:10.3389/fimmu.2020.01613

Cited by 51 publications

(53 citation statements)

References 103 publications

(125 reference statements)

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“… 22 In addition, HLA-G-expressing immune cells such as dendritic cells and T cells have been reported to promote tumor development by inhibiting antitumor immunity. 52 Furthermore, we found that some HLA-G-positive immune cells were present in TNBC, GBM, PA, and OV tumor sections. Thus, another possibility is that the HLA-G CAR-NK may also eliminate these immunosuppressive cells to enhance antitumor immunity in patients.…”

Section: Discussionmentioning

confidence: 75%

Targeting human leukocyte antigen G with chimeric antigen receptors of natural killer cells convert immunosuppression to ablate solid tumors

Jan

Huang

Canoll

et al. 2021

J Immunother Cancer

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BackgroundImmunotherapy against solid tumors has long been hampered by the development of immunosuppressive tumor microenvironment, and the lack of a specific tumor-associated antigen that could be targeted in different kinds of solid tumors. Human leukocyte antigen G (HLA-G) is an immune checkpoint protein (ICP) that is neoexpressed in most tumor cells as a way to evade immune attack and has been recently demonstrated as a useful target for chimeric antigen receptor (CAR)-T therapy of leukemia by in vitro studies. Here, we design and test for targeting HLA-G in solid tumors using a CAR strategy.MethodsWe developed a novel CAR strategy using natural killer (NK) cell as effector cells, featuring enhanced cytolytic effect via DAP12-based intracellular signal amplification. A single-chain variable fragment (scFv) against HLA-G is designed as the targeting moiety, and the construct is tested both in vitro and in vivo on four different solid tumor models. We also evaluated the synergy of this anti-HLA-G CAR-NK strategy with low-dose chemotherapy as combination therapy.ResultsHLA-G CAR-transduced NK cells present effective cytolysis of breast, brain, pancreatic, and ovarian cancer cells in vitro, as well as reduced xenograft tumor growth with extended median survival in orthotopic mouse models. In tumor coculture assays, the anti-HLA-G scFv moiety promotes Syk/Zap70 activation of NK cells, suggesting reversal of the HLA-G-mediated immunosuppression and hence restoration of native NK cytolytic functions. Tumor expression of HLA-G can be further induced using low-dose chemotherapy, which when combined with anti-HLA-G CAR-NK results in extensive tumor ablation both in vitro and in vivo. This upregulation of tumor HLA-G involves inhibition of DNMT1 and demethylation of transporter associated with antigen processing 1 promoter.ConclusionsOur novel CAR-NK strategy exploits the dual nature of HLA-G as both a tumor-associated neoantigen and an ICP to counteract tumor spread. Further ablation of tumors can be boosted when combined with administration of chemotherapeutic agents in clinical use. The readiness of this novel strategy envisions a wide applicability in treating solid tumors.

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Section: Discussionmentioning

confidence: 75%

Targeting human leukocyte antigen G with chimeric antigen receptors of natural killer cells convert immunosuppression to ablate solid tumors

Jan

Huang

Canoll

et al. 2021

J Immunother Cancer

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“…As an essential immune tolerance regulator in the human body, HLA-G5 is involved in processes such as foetal tolerance and autoimmunity during pregnancy, as well as inflammatory diseases and receiving allotransplantation from patients (37,38), and can achieve immune tolerance and protect the human body by interacting with inhibitory receptors on the surface of immune cells. HLA-G can interact with immunoglobulin-like proteins on dendritic cells (DC) (39,40), and through such self-made interactions, can suppress immune cells (41). Importantly, in normal tissues, HLA-G is most abundantly distributed on the surface of trophoblast cells in the placenta, which can effectively inhibit the local immune response in the uterus and promote the tolerance of the mother to the foetus (6,42).…”

Section: Discussionmentioning

confidence: 99%

Novel nucleic acid aptamer gold (Au)-nanoparticles (AuNPs-AptHLA-G5-1 and AuNPs-AptHLA-G5-2) to detect the soluble human leukocyte antigen G5 subtype (HLA-G5) in liquid samples

Wang

Yao

2021

Ann Transl Med

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Background: The human leukocyte antigen G5 subtype (HLA-G5) is a major histocompatibility complex (MHC) molecule that is selectively expressed at the maternal-foetal tissue interface and is required for the successful implantation of the in vitro fertilized embryo. It is critical to detect HLA-G5, especially HLA-G5 expression in embryo fluid, during in vitro embryo incubation and culture. However, the specificity and sensitivity of traditional ELISA methods to detect sHLA-G5 are insufficient. This work aimed to explore novel nucleic acid aptamer gold (Au)-nanoparticles to detect soluble HLA-G5 in liquid samples.Methods: Soluble HLA-G5 was obtained using a prokaryotic expression system, and two novel aptamers (HLA-G5-Apt1 and HLA-G5-Apt2) detecting HLA-G5 were screened by the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) method. Small (10 nm) gold nanoparticles (AuNPs) were incubated with AptHLAs to form two novel nucleic acid aptamers: Au-nanoparticles (AuNPs-AptHLA-G5-1 and AuNPs-AptHLA-G5-2). Results:The results showed that AptHLA-G5-1 and AptHLA-G5-2 have a high affinity for HLA-G5 and can detect its presence in liquid samples. Using the colorimetric sensing method, AuNPs-AptHLA-G1 had a detection limit as low as 20 ng/mL (recovery range between 98.7% to 102.0%), while AuNPs-AptHLA-G2 had a detection limit as low as 20 ng/mL (recovery range between 98.9% to 103.6%).Conclusions: Our work demonstrates that novel AuNPs are efficient detectors for HLA-G5 and are useful for diagnosis and treatment in the field of obstetrics-gynaecology.

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“…HLA-G seems also to be involved in the tuning of immune responses, as incubation of peripheral blood mononuclear cells (PBMC) with HLA-G-expressing cells favors a shift towards a Th-2 cytokine profile, whereas incubation with soluble HLA-G molecules may have a counterbalancing effect by creating an anti-inflammatory environment due to the release of interleukin (IL)-10 (10,11). While originally described as restricted in its constitutive tissue expression (12)(13)(14)(15)(16), HLA-G expression can be induced in several pathologic conditions (17)(18)(19)(20)(21)(22)(23)(24). Of note, cytokines such as interferon (IFN)-g and IL-10 trigger the expression of HLA-G by PBMC.…”

Section: Hla-gmentioning

confidence: 99%

“…HLA-G+ immune cells are present in the peripheral blood of healthy subjects where they probably contribute to maintain immune tolerance. Conversely, increased percentages of circulating and tissue-infiltrating HLA-G+ immune cells (e.g., T and NK cells, monocytes, DCs, mast cells) can be observed in different pathological situations such as infections, cancers, transplants and autoimmune disorders suggesting a potential role for these cells in the pathogenesis of diseases in which immune system is strictly implicated (1,2,24,(36)(37)(38). Based on these findings, it has been proposed that HLA-G should be qualified as an 'immune checkpoint' molecule (39).…”

Section: Hla-gmentioning

confidence: 99%

HLA-G in Allergy: Does It Play an Immunoregulatory Role?

et al. 2022

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Allergy is an inflammatory process determined by a cascade of immune events characterized by T-helper 2 lymphocytes polarization leading to interleukin-4 upregulation, IgE secretion, and mast cell and eosinophil activation. HLA-G molecules, both in membrane-bound and in soluble forms, are known to play a key immunoregulatory role and their involvement in allergic diseases is supported by increasing literature data. HLA-G expression and secretion is specifically induced in peripheral blood mononuclear cells of allergic patients after in vitro incubation with the causal allergen. Elevated levels of soluble HLA-G molecules are detected in serum of patients with allergic rhinitis correlating with allergen-specific IgE levels, clinical severity, drug consumption and response to allergen-specific immunotherapy. HLA-G genetic polymorphisms confer susceptibility to allergic asthma development and high levels of soluble HLA-G molecules are found in plasma and bronchoalveolar lavage fluid of patients with allergic asthma correlating with allergen-specific IgE levels. Interestingly, allergic pregnant women have lower plasma sHLA-G levels than non-allergic women during the 3rd trimester of pregnancy and at delivery. Finally, in allergic patients with atopic dermatitis HLA-G molecules are expressed by T cells, monocytes-macrophages and Langerhans cells infiltrating the dermis. Although at present is difficult to completely define the role of HLA-G molecules in allergic diseases, it may be suggested that they are specifically expressed and secreted by immune cells during the allergic reaction in an attempt to suppress allergic inflammation.

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HLA-G Expressing Immune Cells in Immune Mediated Diseases

Cited by 51 publications

References 103 publications

Targeting human leukocyte antigen G with chimeric antigen receptors of natural killer cells convert immunosuppression to ablate solid tumors

Targeting human leukocyte antigen G with chimeric antigen receptors of natural killer cells convert immunosuppression to ablate solid tumors

Novel nucleic acid aptamer gold (Au)-nanoparticles (AuNPs-AptHLA-G5-1 and AuNPs-AptHLA-G5-2) to detect the soluble human leukocyte antigen G5 subtype (HLA-G5) in liquid samples

HLA-G in Allergy: Does It Play an Immunoregulatory Role?

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