CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset

López‐Vergès, Sandra; Milush, Jeffrey M.; Pandey, Suchitra; York, Vanessa A.; Arakawa-Hoyt, Janice; Pircher, Hanspeter; Norris, Phillip J.; Nixon, Douglas F.; Lanier, Lewis L.

doi:10.1182/blood-2010-04-282301

Cited by 595 publications

(629 citation statements)

References 50 publications

(75 reference statements)

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“…Moreover, IFN-g production by PD-1 1 NK cells in response to exogenous rhIL-12 plus rhIL-18 was highly defective (data not shown). [50][51][52] Thus it is conceivable that PD-1 1 NK cells might represent a population of poorly proliferating cells that could be induced to divide only by high concentrations of microenvironmental cytokines, as suggested by our present data.…”

Section: Discussionsupporting

confidence: 54%

“…53 On the other hand, in line with their high content of perforin/granzyme and their high expression of CD16, PD-1 1 NK cells could degranulate to levels comparable with PD-1 2 cells in response to anti-CD16 mAbs in R-ADCC. [50][51][52] Thus under this experimental condition, the impaired degranulation of PD-1 1 NK cells caused by downregulation of NCRs (NKp30 and NKp46) can be bypassed by a potent stimulus delivered by CD16. Based on the recovery of different functions (cytokine release and cytotoxicity) on cell triggering through CD16 in R-ADCC, it is unlikely that PD-1 1 NK cells merely represent a population of exhausted cells with an intrinsic functional defect.…”

Section: Discussionmentioning

confidence: 89%

“…64 Thus it is conceivable that also human CD57 1 NK cells can be poorly responsive because they express low amounts of CD122 (IL-2 receptor b, a subunit of the shared receptor for IL-2 and IL-15). [50][51][52]65 In addition, the PD-1 1 NK cell subset is characterized by the lowest CD122 expression among CD57 1 NK cells (data not shown). Moreover, IFN-g production by PD-1 1 NK cells in response to exogenous rhIL-12 plus rhIL-18 was highly defective (data not shown).…”

Section: Discussionmentioning

confidence: 91%

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Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

Pesce

Greppi

Tabellini

et al. 2017

Journal of Allergy and Clinical Immunology

363

365

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Background: Programmed death 1 (PD-1) is an immunologic checkpoint that limits immune responses by delivering potent inhibitory signals to T cells on interaction with specific ligands expressed on tumor/virus-infected cells, thus contributing to immune escape mechanisms. Therapeutic PD-1 blockade has been shown to mediate tumor eradication with impressive clinical results. Little is known about the expression/function of PD-1 on human natural killer (NK) cells. Objective: We sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features. Methods: We performed multiparametric cytofluorimetric analysis of PD-1 1 NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays. Results: We provide unequivocal evidence that PD-1 is highly expressed (PD-1 bright ) on an NK cell subset detectable in the peripheral blood of approximately one fourth of healthy subjects. These donors are always serologically positive for human cytomegalovirus. PD-1 is expressed by CD56 dim but not CD56 bright NK cells and is confined to fully mature NK cells characterized by the NKG2A 2 KIR 1 CD57 1 phenotype. Proportions of PD-1 bright NK cells were higher in the ascites of a cohort of patients with ovarian carcinoma, suggesting their

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 91%

See 1 more Smart Citation

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

Pesce

Greppi

Tabellini

et al. 2017

Journal of Allergy and Clinical Immunology

363

365

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“…PD-L1 blockade also resulted in higher amounts of CD57 + NK cells, a subpopulation that have been reported to have a higher cytotoxic capacity with greater responsiveness via CD16 engagement and its presence correlated with better outcomes in squamous cell lung cancer. 40,41 …”

Section: Discussionmentioning

confidence: 99%

PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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Anti-PD-1/anti-PD-L1 therapies have shown success in cancer treatment but responses are limited to ~ 15% of patients with lymphocyte infiltrated, PD-L1 positive tumors. Hence, strategies that increase PD-L1 expression and tumor infiltration should make more patients eligible for PD-1/PD-L1 blockade therapy, thus improving overall outcomes. PD-L1 expression on tumors is induced by IFNγ, a cytokine secreted by NK cells. Therefore, we tested if PM21-particle expanded NK cells (PM21-NK cells) induced expression of PD-L1 on tumors and if anti-PD-L1 treatment enhanced NK cell anti-tumor efficacy in an ovarian cancer model. Studies here showed that PM21-NK cells secrete high amounts of IFNγ and that adoptively transferred PM21-NK cells induce PD-L1 expression on SKOV-3 cells in vivo. The induction of PD-L1 expression on SKOV-3 cells coincided with the presence of regulatory T cells (Tregs) in the abdominal cavity and within tumors. In in vitro experiments, anti-PD-L1 treatment had no direct effect on cytotoxicity or cytokine secretion by predominantly PD-1 negative PM21-NK cells in response to PD-L1+ targets. However, significant improvement of NK cell anti-tumor efficacy was observed in vivo when combined with anti-PD-L1. PD-L1 blockade also resulted in increased in vivo NK cell persistence and retention of their cytotoxic phenotype. These results support the use of anti-PD-L1 in combination with NK cell therapy regardless of initial tumor PD-L1 status and indicate that NK cell therapy would likely augment the applicability of anti-PD-L1 treatment.

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“…Of note, CD57 is expressed only by a subset of CD56 dim NK cells and by a small subpopulation of T cells. On NK cells, CD57 expression correlates with high expression of inhibitory KIRs, low expression of the activating receptors NKp30, NKp46 and NKG2D and of the cytokine receptor chains IL-2Rβ and IL-12Rβ [104,105]. Functionally, CD57 + NK cells display reduced proliferative capacity, but are potent IFN-γ producers and show high lytic capacity when stimulated via CD16.…”

Section: Nk Cell Recruitment To the Tumor Sitementioning

confidence: 99%

Shaping of NK Cell Responses by the Tumor Microenvironment

Stojanović

Correia

Cerwenka

2012

Cancer Microenvironment

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Natural killer (NK) cells belong to the innate immune system and are potent cytolytic and cytokineproducing effector cells in response to tumor targets. NK cell based anti-tumor immunotherapy was so far mainly successful in patients with different types of leukemia. For instance, acute myeloid leukemia (AML) patients displayed a prolonged survival if transplanted with haploidentical stem cells giving rise to NK cells with a mismatch in inhibitory killer immunoglobulin receptors (KIRs) and recipients' HLA class I. Although promising results have been achieved with hematological tumors, solid tumors are in most cases poorly controlled by NK cells. Therapeutic protocols that aimed at improving NK cell responses in patients with solid malignancies succeeded in increasing NK cell numbers and functional responses of NK cells isolated from the patients' peripheral blood. However, in the majority of cases tumor progression and overall survival of patients were not significantly improved. There is increasing evidence that tumor-associated NK cells become gradually impaired during tumor progression compared to NK cells from peripheral blood and healthy tissues. Future protocols of NK cell based immunotherapy should integrate three important aspects to improve NK cell anti-tumor activity: facilitating NK cell migration to the tumor site, enhancing their infiltration into the tumor tissue and ensuring subsequent efficient activation in the tumor. This review summarizes the current knowledge of tumor-infiltrating NK cells and the influence of the tumor microenvironment on their phenotype and function.

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CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset

Cited by 595 publications

References 50 publications

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

PD-L1 blockade enhances anti-tumor efficacy of NK cells

Shaping of NK Cell Responses by the Tumor Microenvironment

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