Effect of frequently used chemotherapeutic drugs on the cytotoxic activity of human natural killer cells

Márkász, László; Stuber, György; Vanherberghen, Bruno; Flaberg, Emilie; Oláh, Éva; Carbone, Ennio; Eksborg, Staffan; Klein, Eva; Skribek, Henriette; Szekeres, L.

doi:10.1158/1535-7163.mct-06-0358

Cited by 101 publications

(87 citation statements)

References 50 publications

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“…Furthermore, patients showing a pathologic response tended to show an increased number of infiltrating NK cells compared with poor or nonresponders. While no difference was seen in the number of infiltrating CD56þ NK in a trial of patients with CRC treated with cetuximab compared with noncetuximab-treated patients, tumor-infiltrating CD56þ cells were an independent predictor of PFS and response only in patients treated with cetuximab-based therapies (48). The immune cell infiltration seen with GA201, together with the very significant efficacy difference observed between the glycoengineered GA201 and its wild-type nonglycoengineered version, suggest that the in vivo efficacy of GA201 in such models is likely attributable to the superior immune effector functions of GA201 resulting from an increased binding affinity to FcgRIV and FcgRIIIA on infiltrating mouse monocytes, macrophages and NK cells.…”

Section: Discussionmentioning

confidence: 89%

GA201 (RG7160): A Novel, Humanized, Glycoengineered Anti-EGFR Antibody with Enhanced ADCC and Superior In Vivo Efficacy Compared with Cetuximab

Gerdes

Nicolini

Herter

et al. 2013

Clinical Cancer Research

111

109

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Purpose: Anti-EGF receptor (EGFR) antibodies and small-molecule tyrosine kinase inhibitors have shown activity in epithelial tumors; however, agents that work by blocking the EGFR growth signal are ineffective when the oncogenic stimulus arises downstream, such as in tumors with KRAS mutations. Antibodies of the IgG 1 subclass can also kill tumor cells directly through antibody-dependent cell-mediated cytotoxicity (ADCC), and the efficacy of this is determined by the interaction of the Fc portion of the target cell-bound antibody and Fc receptors present on immune effector cells.Experimental Design: We report the development of GA201, a novel anti-EGFR monoclonal antibody with enhanced ADCC properties. GA201 was derived by humanization of the rat ICR62 antibody. The Fc region of GA201 was glycoengineered to contain bisected, afucosylated carbohydrates for enhanced binding to FcgRIIIA.Results: In vitro binding of GA201 to EGFR inhibited EGF ligand binding, EGFR/HER2 heterodimerization, downstream signaling, and cell proliferation to a similar extent as cetuximab. However, GA201 exhibited superior binding to both the low-and high-affinity variants of FcgRIIIA. This resulted in significantly enhanced induction of ADCC compared with cetuximab against both KRAS-wild-type and -mutant tumor cells lines. This enhanced ADCC translated into superior in vivo efficacy in a series of mouse xenograft models. Efficacy of GA201 was further increased when administered in combination with chemotherapy (irinotecan).Conclusions: These data suggest that GA201 may be more effective than cetuximab in patients with EGFR-positive solid tumors and may also represent a first-in-class treatment of patients with KRAS-mutated tumors.

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Section: Discussionmentioning

confidence: 89%

GA201 (RG7160): A Novel, Humanized, Glycoengineered Anti-EGFR Antibody with Enhanced ADCC and Superior In Vivo Efficacy Compared with Cetuximab

Gerdes

Nicolini

Herter

et al. 2013

Clinical Cancer Research

111

109

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“…As mentioned above, high doses of Bortezomib have been reported to inhibit NK cell cytotoxicity (12), which could potentially counteract the observed beneficial effects of MIC induction on the hepatoma cells. Therefore, we treated primary NK cells of healthy donors with different concentrations of Bortezomib for 24 hours and examined NK cell cytotoxicity and IFN-g production in response to K562 target cells, which are the classic target cells for studying NK cell functions.…”

Section: Resultsmentioning

confidence: 95%

“…Although these promising reports suggested a potentially selective effect of Bortezomib on hepatoma cells, a recent study described that high concentrations of Bortezomib inhibited natural killer (NK) cell cytotoxicity (12). These observations raise the concern that a potential antitumor effect of Bortezomib in the context of HCC might be annulled by a negative influence on immune effector cells such as NK cells.…”

mentioning

confidence: 99%

Direct and Natural Killer Cell-Mediated Antitumor Effects of Low-Dose Bortezomib in Hepatocellular Carcinoma

Armeanu

Krusch²,

Baltz³

et al. 2008

Clinical Cancer Research

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Purpose: Hepatocellular carcinoma (HCC) displays particular resistance to conventional cytostatic agents. Alternative treatment strategies focus on novel substances exhibiting antineoplastic and/or immunomodulatory activity enhancing for example natural killer (NK) cell antitumor reactivity. However, tumor-associated ligands engaging activating NK cell receptors are largely unknown. Exceptions are NKG2D ligands (NKG2DL) of the MHC class I-related chain and UL16-binding protein families, which potently stimulate NK cell responses. We studied the consequences of proteasome inhibition with regard to direct and NK cell^mediated effects against HCC. Experimental Design: Primary human hepatocytes (PHH) from different donors, hepatoma cell lines, and NK cells were exposed to Bortezomib. Growth and viability of the different cells, and immunomodulatory effects including alterations of NKG2DL expression on hepatoma cells, specific induction of NK cell cytotoxicity and IFN-g production were investigated. Results: Bortezomib treatment inhibited hepatoma cell growth with IC 50 values between 2.4 and 7.7 nmol/L. These low doses increased MICA/B mRNA levels, resulting in an increase of total and cell surface protein expression in hepatoma cells, thus stimulating cytotoxicity and IFN-g production of cocultured NK cells. Importantly, although NK cell IFN-g production was concentration-dependently reduced, low-dose Bortezomib neither induced NKG2DL expression or cell death in PHH nor altered NK cell cytotoxicity. Conclusions: Low-dose Bortezomib mediates a specific dual antitumor effect in HCC by inhibiting tumor cell proliferation and priming hepatoma cells for NK cell antitumor reactivity. Our data suggest that patients with HCC may benefit from Bortezomib treatment combined with immunotherapeutic approaches such as adoptive NK cell transfer taking advantage of enhanced NKG2D-mediated antitumor immunity.

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“…Indeed, an 11-y follow-up population study of 3625 people $40 y of age demonstrated that the potency of NK cells in peripheral blood to lyse tumor cell targets is inversely associated with cancer risk (48). Further, delayed acquisition of NK cell cytolytic function following cancer therapy may contribute to recurrent disease (49). Perhaps most intriguing is recent evidence that PTEN can be secreted in exosomes and that the exported PTEN retains its lipid phosphatase ability upon entering the recipient cell (50).…”

Section: Discussionmentioning

confidence: 99%

PTEN Is a Negative Regulator of NK Cell Cytolytic Function

Briercheck

Trotta

Chen

et al. 2015

The Journal of Immunology

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Human NK cells are characterized by their ability to initiate an immediate and direct cytolytic response to virally infected or malignantly transformed cells. Within human peripheral blood, the more mature CD56dim NK cell efficiently kills malignant targets at rest, whereas the less mature CD56bright NK cells cannot. In this study, we show that resting CD56bright NK cells express significantly more phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein when compared with CD56dim NK cells. Consistent with this, forced overexpression of PTEN in NK cells resulted in decreased cytolytic activity, and loss of PTEN in CD56bright NK cells resulted in elevated cytolytic activity. Comparable studies in mice showed PTEN overexpression did not alter NK cell development or NK cell–activating and inhibitory receptor expression yet, as in humans, did decrease expression of downstream NK activation targets MAPK and AKT during early cytolysis of tumor target cells. Confocal microscopy revealed that PTEN overexpression disrupts the NK cell’s ability to organize immunological synapse components including decreases in actin accumulation, polarization of the microtubule organizing center, and the convergence of cytolytic granules. In summary, our data suggest that PTEN normally works to limit the NK cell’s PI3K/AKT and MAPK pathway activation and the consequent mobilization of cytolytic mediators toward the target cell and suggest that PTEN is among the active regulatory components prior to human NK cells transitioning from the noncytolytic CD56bright NK cell to the cytolytic CD56dim NK cells.

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Effect of frequently used chemotherapeutic drugs on the cytotoxic activity of human natural killer cells

Cited by 101 publications

References 50 publications

GA201 (RG7160): A Novel, Humanized, Glycoengineered Anti-EGFR Antibody with Enhanced ADCC and Superior In Vivo Efficacy Compared with Cetuximab

GA201 (RG7160): A Novel, Humanized, Glycoengineered Anti-EGFR Antibody with Enhanced ADCC and Superior In Vivo Efficacy Compared with Cetuximab

Direct and Natural Killer Cell-Mediated Antitumor Effects of Low-Dose Bortezomib in Hepatocellular Carcinoma

PTEN Is a Negative Regulator of NK Cell Cytolytic Function

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