Regulation of the Functions of Natural Cytotoxicity Receptors by Interactions with Diverse Ligands and Alterations in Splice Variant Expression

Pazina, Tatiana; Shemesh, Avishai; Brusilovsky, Michael; Porgador, Angel; Campbell, Kerry S.

doi:10.3389/fimmu.2017.00369

Cited by 63 publications

(58 citation statements)

References 113 publications

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“…Notably, splice variants of human NCR encoding receptor isoforms with inhibitory functions have been recently discovered, 39 influencing outcomes in many immunopathological contexts. 40 Such differential splicing arises in some tissue microenvironments where inhibitory NCR are triggered by specific ligands, as this is the case for the inhibitory isoform of NKp44 that cross-link Proliferating Cell Nuclear Antigen (PCNA) on tumor cells, a ligand expressed by many cancer types. Interestingly, the inhibitory form of NKp44 has been found on tumor-infiltrating NK cells, 40 and blocking the interaction NKp44-PCNA results in inhibition of tumor growth including melanoma in mouse models.…”

Section: Discussionmentioning

confidence: 99%

“…40 Such differential splicing arises in some tissue microenvironments where inhibitory NCR are triggered by specific ligands, as this is the case for the inhibitory isoform of NKp44 that cross-link Proliferating Cell Nuclear Antigen (PCNA) on tumor cells, a ligand expressed by many cancer types. Interestingly, the inhibitory form of NKp44 has been found on tumor-infiltrating NK cells, 40 and blocking the interaction NKp44-PCNA results in inhibition of tumor growth including melanoma in mouse models. 41 Hence, NCR can be considered as novel innate immune checkpoints, which, based on our results, offer an exciting potential therapeutic target to manipulate in cancer.…”

Section: Discussionmentioning

confidence: 99%

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The features of circulating and tumor-infiltrating γδ T cells in melanoma patients display critical perturbations with prognostic impact on clinical outcome

et al. 2019

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γδT cells hold a pivotal role in tumor immunosurveillance through their prompt activation and cytokine secretion, their ability to kill tumor cells in an Human Leukocyte Antigen (HLA)-unrestricted manner, and their combination of features of both innate and adaptive immunity. These unique properties and functional plasticity render them very attractive both as targets and vectors for cancer immunotherapy. Yet, these potent and fascinating antitumor effectors have not been extensively explored in melanoma. We provided here a detailed investigation of the phenotypic and functional properties of circulating and tumor-infiltrating γδT cells in melanoma patients, and their impact on clinical evolution. High proportions of circulating-and tumor-infiltrating γδT and δ2+ subset were associated with better clinical outcome. We reported however that circulating and tumor-infiltrating γδT cells from melanoma patients displayed an altered expression of NCR, KIR, and immune checkpoints, and identified NKp44, PD1, 41BB/ 41BBL, TIM3, and LAG3 as crucial checkpoints allowing immune escape and tumor progression. Notably, melanoma drastically impaired the ability of γδT cells to exhibit activation molecules, secrete cytokines, and display cytotoxicity toward melanoma in response to stimulation with phosphoantigens. It drove them toward regulatory and Th17 profiles associated with poor clinical outcomes. Our study highlights that melanoma hijacked γδT cells to escape from immune control, and revealed that circulating and tumor-infiltrating γδT cell features are promising potential biomarkers of clinical evolution. Such understanding of the physiopathology of γδT cells may help designing new therapeutic approaches exploiting the antitumor potential of γδT cells while counteracting their skewing by tumors to improve patient outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The features of circulating and tumor-infiltrating γδ T cells in melanoma patients display critical perturbations with prognostic impact on clinical outcome

et al. 2019

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“…In addition, mice lack the expression of NKp44 and NKp30; however, NKp30 is an unexpressed pseudogene in mice (60,61). Although some ligands for activating and inhibitory receptors are known today, the family of ligands is not yet fully elucidated (62).…”

Section: Introductionmentioning

confidence: 99%

Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

et al. 2020

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Obesity is accompanied by a systemic chronic low-grade inflammation as well as dysfunctions of several innate and adaptive immune cells. Recent findings emphasize an impaired functionality and phenotype of natural killer (NK) cells under obese conditions. This review provides a detailed overview on research related to overweight and obesity with a particular focus on NK cells. We discuss obesity-associated alterations in subsets, distribution, phenotype, cytotoxicity, cytokine secretion, and signaling cascades of NK cells investigated in vitro as well as in animal and human studies. In addition, we provide recent insights into the effects of physical activity and obesity-associated nutritional factors as well as the reduction of body weight and fat mass on NK cell functions of obese individuals. Finally, we highlight the impact of impaired NK cell physiology on obesity-associated diseases, focusing on the elevated susceptibility for viral infections and increased risk for cancer development and impaired treatment response.NK cells are large granular lymphocytes that mediate rapid innate immunity against viruses, bacteria, parasites, and tumor cells without prior sensitization. NK cells primarily develop and mature in the bone marrow, migrate through the bloodstream, and seed into secondary lymphoid organs, like thymus, spleen, and lymph nodes as well as in other peripheral tissues, like lung, liver, kidney, uterus, and the gastrointestinal tract (23). In blood, NK cells represent 1-6% of all leukocytes and comprise up to 15% of human peripheral blood mononuclear cells (PBMCs). Human NK cells have been defined by the expression of adhesion molecule CD56 and by the absence of the T cell marker CD3. Based on their expression level of CD56 and the Fcγ receptor CD16, NK cells are subdivided into different subpopulations. The two major and classically defined subsets are the CD56 dim CD16 bright NK cells and the CD56 bright CD16 dim/neg NK cells. CD56 dim CD16 bright NK cells represent about 90% of all NK cells and are predominantly found in peripheral blood (24). They are mostly responsible for cytotoxic activity and target cell killing but are also a source of pro-inflammatory Abbreviations: ACM, adipocyte-conditioned media; Adamts3, a disintegrin-like and metallopeptidase with thrombospondin type 1 motif, 3; AdipoR, adiponectin receptor; Anxa8, annexin A8; AT, adipose tissue; Bax, Bcl-2-associated X protein; Bcl, B-cell lymphoma; BMI, body mass index; CCR, CC chemokine receptor; Csf1r, colony stimulating factor 1 receptor; CX3CR1, C-X3-C-motif chemokine receptor 1; DNAM-1, DNAX accessory molecule-1; ESR, estrogen receptor; FasL, Fas ligand; IFN-γ, interferon; GM-CSF; granulocyte macrophage colony-stimulating factor; H6pd, hexose-6-phosphate dehydrogenase; Hk2, hexokinase 2; IL, interleukinIL-6R; interleukin-6 receptor; Il18rap, interleukin 18 receptor accessory protein; IP-10, interferon gamma-induced protein 10; JAK, Janus kinase; KIR, killer immunoglobulin-like receptor; Klra1, killer lectin-like receptor subfamil...

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“…B7-H6 interacts with its front β-sheet of the V-like domain with the front and back β-sheets of C-like domain of NKp30 [34]. B7-H6 surface expression is restricted to both primary tumors and tumor cell lines, while neither healthy nor stressed cells appear to express B7-H6 [31,54,55]. Expression of B7-H6 on the surface of tumor cells enhances NKp30-mediated killing by NK cells [32].…”

Section: B7-h6mentioning

confidence: 99%

The Antitumor Immunity Mediated by NK Cells: The Role of The NCRs

Rady¹,

Abou-Aisha²

2018

TOCIJ

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Natural Killer (NK) cells are innate immune lymphocytes that are important for early and effective immune responses against infections and cancer. The antitumor immunity mediated by NK cells can be exerted through several direct or indirect “immunosurveillance” mechanisms that control tumor growth and prevent the rapid dissemination of metastatic tumors. NK cells express an array of activating and inhibitory receptors that enable them to recognize and bind non-self as well as self-ligands expressed on the surface of malignant or virally infected cells. The family of Natural Cytotoxicity Receptors (NCRs) comprises three activating receptors; NKp30, NKp44, and NKp46 that are important for the stimulation of NK cell effector functions. This review summarizes the mechanisms of antitumor immunity mediated by natural killer cells with focus on the role of the family of the NCRs and their tumor associated ligands.

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Regulation of the Functions of Natural Cytotoxicity Receptors by Interactions with Diverse Ligands and Alterations in Splice Variant Expression

Cited by 63 publications

References 113 publications

The features of circulating and tumor-infiltrating γδ T cells in melanoma patients display critical perturbations with prognostic impact on clinical outcome

The features of circulating and tumor-infiltrating γδ T cells in melanoma patients display critical perturbations with prognostic impact on clinical outcome

Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

The Antitumor Immunity Mediated by NK Cells: The Role of The NCRs

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