The Stage Dependent Changes in NK Cell Activity and the Expression of Activating and Inhibitory NK Cell Receptors in Melanoma Patients

Martinović, Katarina Mirjačić; Konjević, Gordana; Babović, Nada; Inić, M.

doi:10.1016/j.jss.2010.05.012

Cited by 19 publications

(21 citation statements)

References 49 publications

(57 reference statements)

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“…For different neoplasias decrease in NK cell cytotoxicity has been described to be stage-dependent. For patients with lymphoma, melanoma, and head and neck cancer, a more advanced, e.g., metastatic/disseminated disease was associated with lower NK cell lytic activity compared to patients with localized, early-stage disease 9,10,60 . Of the 11 2nd-line STS patients in our study, seven had metastatic disease, while none of the patients in the 1st-line cohort had evidence of metastasis.…”

Section: Discussionmentioning

confidence: 60%

Progressive natural killer cell dysfunction associated with alterations in subset proportions and receptor expression in soft-tissue sarcoma patients

et al. 2016

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Immunotherapy is currently investigated as treatment option in many types of cancer. So far, results from clinical trials have demonstrated that significant benefit from immunomodulatory therapies is restricted to patients with select histologies. To broaden the potential use of these therapies, a deeper understanding for mechanisms of immunosuppression in patients with cancer is needed. Soft-tissue sarcoma (STS) presents a medical challenge with significant mortality even after multimodal treatment. We investigated function and immunophenotype of peripheral natural killer (NK) cells from chemotherapy-naive STS patients (1st line) and STS patients with progression or relapse after previous chemotherapeutic treatment (2nd line). We found NK cells from peripheral blood of both STS patient cohorts to be dysfunctional, being unable to lyse K562 target cells while NK cells from renal cell cancer (RCC) patients did not display attenuated lytic activity. Ex vivo stimulation of NK cells from STS patients with interleukin-2 plus TKD restored cytotoxic function. Furthermore, altered NK cell subset composition with reduced proportions of CD56dim cells could be demonstrated, increasing from 1st- to 2nd-line patients. 2nd-line patients additionally displayed significantly reduced expression of receptors (NKG2D), mediators (CD3ζ), and effectors (perforin) of NK cell activation. In these patients, we also detected fewer NK cells with CD57 expression, a marker for terminally differentiated cytotoxic NK cells. Our results elucidate mechanisms of NK cell dysfunction in STS patients with advanced disease. Markers like NKG2D, CD3ζ, and perforin are candidates to characterize NK cells with effective antitumor function for immunotherapeutic interventions.

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Section: Discussionmentioning

confidence: 60%

Progressive natural killer cell dysfunction associated with alterations in subset proportions and receptor expression in soft-tissue sarcoma patients

et al. 2016

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“…Compared to donors, a decreased expression of the activating NKG2D receptor and an increased expression of the inhibitory KIR, CD158b, were described on NK cells from metastatic melanoma patients and correlated with an impaired NK cell function [19]. The combined CD161 low /NKG2D low expression was reported and correlated with the altered cytokine-induced NK cell activity in metastatic melanoma patients [20], [21].…”

Section: Discussionmentioning

confidence: 94%

Phenotypic and Functional Characteristics of Blood Natural Killer Cells from Melanoma Patients at Different Clinical Stages

et al. 2013

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Melanomas are aggressive skin tumors characterized by high metastatic potential. Immunotherapy is a valuable alternative for metastatic melanoma patients resistant to chemotherapy. Natural Killer (NK) cells are efficient anti-tumor cytotoxic effectors. We previously showed that blood NK cells from stage IV metastatic melanoma patients display decreased NK receptors and that chemotherapy modifies the functional status of blood NK cells. To investigate the role of NK cells along melanoma progression, we have here studied NK cells from patients at different stages of the disease. First, we showed that ex vivo NK cells from certain stage III–IV patients displayed low degranulation potential. Using a dynamic label-free assay, we found that immunoselected IL-2 activated blood NK cells from patients efficiently lysed melanoma cells through NKp46 and NKG2D receptors, independently to the clinical stage. Moreover, the ex vivo phenotype of circulating NK cells from 33 patients (stage I to IV) was extensively analyzed. NK cells from patients displayed higher variability in the percentages of Natural Cytotoxicity Receptors (NCR) and Natural Killer Group 2D (NKG2D) receptor expression compared to donor NK cells. The main defect was the decreased expression of NCR1 (NKp46) by NK cells from metastatic patients. Interestingly, we found a positive correlation between the NK cell percentages of NKp46 and the duration of stage IV in melanoma patients. Finally, we showed that NK cells infiltrated primary melanomas and displayed a predominant peritumoral distribution. These results are new arguments for the development of NK-based therapies in melanoma patients.

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“…IFN-γ was analysed in the supernatants using ELISA kit (eBioscience, San Diego, USA) according to the manufacturer's protocol 23. The concentration of IFN-γ was calculated from the colorimetric optical density (model 2550EIA Reader; Bio-Rad, Richmond, USA), which was read at 450 nm.…”

Section: Methodsmentioning

confidence: 99%

Decreased expression of pSTAT, IRF-1 and DAP10 signalling molecules in peripheral blood lymphocytes of patients with metastatic melanoma

et al. 2015

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The Stage Dependent Changes in NK Cell Activity and the Expression of Activating and Inhibitory NK Cell Receptors in Melanoma Patients

Cited by 19 publications

References 49 publications

Progressive natural killer cell dysfunction associated with alterations in subset proportions and receptor expression in soft-tissue sarcoma patients

Progressive natural killer cell dysfunction associated with alterations in subset proportions and receptor expression in soft-tissue sarcoma patients

Phenotypic and Functional Characteristics of Blood Natural Killer Cells from Melanoma Patients at Different Clinical Stages

Decreased expression of pSTAT, IRF-1 and DAP10 signalling molecules in peripheral blood lymphocytes of patients with metastatic melanoma

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