Implications of NKG2A in immunity and immune-mediated diseases

Wang, Xiaotong; Xiong, Huabao; Ning, Zhaochen

doi:10.3389/fimmu.2022.960852

Cited by 39 publications

(28 citation statements)

References 135 publications

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“…NKG2A is also involved in the pathological processes of immune-mediated diseases such as autoimmune diseases, inflammatory diseases, parasitic infections, and transplant rejection. These findings suggest that NKG2A is a novel therapeutic target for various immune-mediated diseases ( 131 , 132 ).…”

Section: Car-nk Cell and Immune Checkpoint Therapiesmentioning

confidence: 88%

Clinical application and prospect of immune checkpoint inhibitors for CAR-NK cell in tumor immunotherapy

Yang

Zhao²,

Sun³

et al. 2023

Front. Immunol.

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Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells is an attractive research field in tumor immunotherapy. While CAR is genetically engineered to express certain molecules, it retains the intrinsic ability to recognize tumor cells through its own receptors. Additionally, NK cells do not depend on T cell receptors for cytotoxic killing. CAR-NK cells exhibit some differences to CAR-T cells in terms of more precise killing, numerous cell sources, and increased effectiveness in solid tumors. However, some problems still exist with CAR-NK cell therapy, such as cytotoxicity, low transfection efficiency, and storage issues. Immune checkpoints inhibit immune cells from performing their normal killing function, and the clinical application of immune checkpoint inhibitors for cancer treatment has become a key therapeutic strategy. The application of CAR-T cells and immune checkpoint inhibitors is being evaluated in numerous ongoing basic research and clinical studies. Immune checkpoints may affect the function of CAR-NK cell therapy. In this review, we describe the combination of existing CAR-NK cell technology with immune checkpoint therapy and discuss the research of CAR-NK cell technology and future clinical treatments. We also summarize the progress of clinical trials of CAR-NK cells and immune checkpoint therapy.

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Section: Car-nk Cell and Immune Checkpoint Therapiesmentioning

confidence: 88%

Clinical application and prospect of immune checkpoint inhibitors for CAR-NK cell in tumor immunotherapy

Yang

Zhao²,

Sun³

et al. 2023

Front. Immunol.

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“…Finally, CD159a is constantly expressed by a lower percentage of immature, mature and hypermature NK cells in the AML group, but the level of expression is higher in all three subpopulations. One might speculate that the upregulation of these inhibitory receptors is tumor-induced, since it is known that iKIRs are strongly associated with NK licensing and ability to limit the immune response and CD94/NKG2A receptor delivers inhibitory signals in both NK cells and CD8+ T cells via interaction with its cognate ligand, HLA-E ( 76 , 77 ).…”

Section: Discussionmentioning

confidence: 99%

“…There are many literature data available showing that tumor cells are able to modulate the expression of key surface proteins in order to evade immune responses, and this stands true for hematological malignancies, as well as for solid tumors ( 76 , 80–82 ). In our study, we have shown that in AML, all in all, the inhibitory receptors displayed a general increased expression on all NK subpopulations.…”

Section: Discussionmentioning

confidence: 99%

Combined flow cytometry natural killer immunophenotyping and KIR/HLA-C genotyping reveal remarkable differences in acute myeloid leukemia patients, but suggest an overall impairment of the natural killer response

Cianga

Rusu²,

Pavel-Tanasa³

et al. 2023

Front. Med.

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IntroductionNatural killer (NK) cells are key anti-tumor effectors of the innate immunity. Phenotypic differences allow us to discriminate in between three functional stages of maturation, named immature, mature and hypermature that are distinctive in terms of receptor expression, cytokine secretion, cytotoxic properties and organ trafficking. NKs display an impressive repertoire of highly polymorphic germline encoded receptors that can be either activating, triggering the effector’s function, or inhibitory, limiting the immune response. In our study, we have investigated peripheral blood NK cells of acute myeloid leukemia (AML) patients.MethodsThe Killer Immunoglobulin-like receptors (KIRs) and the HLA-C genotypes were assessed, as HLA-C molecules are cognate antigens for inhibitory KIRs.ResultsThe AA mainly inhibitory KIR haplotype was found in a higher proportion in AML, while a striking low frequency of the 2DS3 characterized the mainly activating Bx haplotype. Flow cytometry immunophenotyping evidenced a lower overall count of NK cells in AML versus healthy controls, with lower percentages of the immature and mature subpopulations, but with a markedly increase of the hypermature NKs. The analysis of the KIR2DL1, KIR2DL2, KIR2DL3, KIR3DL1, and NKG2A inhibitory receptors surface expression revealed a remarkable heterogeneity. However, an overall trend for a higher expression in AML patients could be noticed in all maturation subpopulations. Some of the AML patients with complex karyotypes or displaying a FLT3 gene mutation proved to be extreme outliers in terms of NK cells percentages or inhibitory receptors expression.DiscussionWe conclude that while the genetic background investigation in AML offers important pieces of information regarding susceptibility to disease or prognosis, it is flow cytometry that is able to offer details of finesse in terms of NK numbers and phenotypes, necessary for an adequate individual evaluation of these patients.

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“…NKG2A, an inhibitory regulator in the NKG2 family of proteins, is an important immune checkpoint for both CD8 + T cells and NK cells. Similar to other immune checkpoints, NKG2A binds to its ligand, peptide-presenting human leukocyte antigen-E (HLA-E), to activate inhibitory signals ( 78 ). The expression pattern of NKG2A in CD8 + T cells is highly regulated.…”

Section: Engineering Strategies To Enhance Antitumor Efficacymentioning

confidence: 99%

“…NKG2A is present in about half of the human peripheral blood NK cells. Although NKG2/CD94 activation has a restrictive effect on the cytotoxicity of NK cells, interrupting the receptor-ligand interaction with HLA-E reinvigorates NK killing ( 78 ). Tumors often overexpress HLA-E and are thus able to suppress NK antitumor activity.…”

Section: Engineering Strategies To Enhance Antitumor Efficacymentioning

confidence: 99%

Genetic engineering strategies to enhance antitumor reactivity and reduce alloreactivity for allogeneic cell-based cancer therapy

et al. 2023

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The realm of cell-based immunotherapy holds untapped potential for the development of next-generation cancer treatment through genetic engineering of chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapies for targeted eradication of cancerous malignancies. Such allogeneic “off-the-shelf” cell products can be advantageously manufactured in large quantities, stored for extended periods, and easily distributed to treat an exponential number of cancer patients. At current, patient risk of graft-versus-host disease (GvHD) and host-versus-graft (HvG) allorejection severely restrict the development of allogeneic CAR-T cell products. To address these limitations, a variety of genetic engineering strategies have been implemented to enhance antitumor efficacy, reduce GvHD and HvG onset, and improve the overall safety profile of T-cell based immunotherapies. In this review, we summarize these genetic engineering strategies and discuss the challenges and prospects these approaches provide to expedite progression of translational and clinical studies for adoption of a universal cell-based cancer immunotherapy.

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Implications of NKG2A in immunity and immune-mediated diseases

Cited by 39 publications

References 135 publications

Clinical application and prospect of immune checkpoint inhibitors for CAR-NK cell in tumor immunotherapy

Clinical application and prospect of immune checkpoint inhibitors for CAR-NK cell in tumor immunotherapy

Combined flow cytometry natural killer immunophenotyping and KIR/HLA-C genotyping reveal remarkable differences in acute myeloid leukemia patients, but suggest an overall impairment of the natural killer response

Genetic engineering strategies to enhance antitumor reactivity and reduce alloreactivity for allogeneic cell-based cancer therapy

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