Anti-tumor activity of ex vivo expanded cytokine-induced killer cells against human hepatocellular carcinoma

Kim, Hwan Mook; Lim, Jaeseung; Yoon, Yeo Dae; Ahn, Ji Mi; Kang, Jong Soon; Lee, Kiho; Park, Song Kyu; Jeong, Young Jin; Kim, Jin Man; Han, Gyoonhee; Yang, Kyu Hwan; Kim, Yeon Jin; Kim, Youngsoo; Han, Sang Bae

doi:10.1016/j.intimp.2007.08.007

Cited by 42 publications

(33 citation statements)

References 34 publications

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“…Immunophenotyping the expanded cells using flow cytometry found CD3 + CD56 + subpopulations of 26.08% and 26.21% in experimental groups 3 and 4, respectively, with the highest result being sample 2 in group 4 after a 14-day culture, with a 32.88% CD3 + CD56 + subpopulation; these percentages are in accordance with previous studies on CD3 + CD56 + CIK cell culture from cord blood samples (Introna et al, 2006;Zhang et al, 2014;Zhang et al, 2015). After 14-21 days in the culture, the number of CD3 + CD56 + cells increased by well over a hundred fold, also in accordance with prior reports, which demonstrate that these cells can be expanded up to one thousand fold from both cord blood MNCs (Introna et al, 2006) and peripheral blood MNCs (Hoyle et al, 1998;Kim et al, 2007a;Kim et al, 2007b;Olioso et al, 2009). …”

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confidence: 91%

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Culture and differentiation of cytokine-induced killer cells from umbilical cord blood-derived mononuclear cells

Duong

et al. 2016

Biomed Res Ther

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Abstract-Cytokine-induced killer cells (CIK) are cytotoxic T cells, which have both NK and T cell properties. These cells are characterized by potent, non-MHC-restricted cytotoxicity and reduced alloreactivity, which make them appealing for use in adoptive immunotherapy of cancer and virus infections. In this study, CIK cells were generated by stimulating umbilical cord blood-derived mononuclear cells (UCB-MNCs) with interferon-gamma (IFN-) on day 0. Anti-CD3 antibody and interleukin-2 (IL-2) were added after 24 hours at four different experimental concentration combinations in order to identify the optimal cytokine amounts for CIK cell proliferation. Cells were collected at four time points over a 21-day period (day 0, 7, 14, 21) for analysis of cell marker presentation using flow cytometry, as well as transcription-level cytokine production using RT-PCR. The results showed that in the 21-day culture, the average final expansion levels of CD3 + CD56 + CIK cell were in the range of hundredfold, accounted for 26% in the bulk culture. Most important, these cells strongly expressed granzyme B (80.87%), a potent factor involved in cell-mediated cytotoxicity. These CIK cells also transcriptionally overexpressed the three cytokine genes that produce IFN-, tumor necrosis factor-alpha (TNF-), and IL-2; these are key for immune cell mobilization against tumors as well as foreign pathogens. Our research establishes an effective cytokine concentration and time protocol for use in generation of CIK cells from UCB-MNCs, potentiating greater applications of CIK cell-adoptive immunotherapy in both research and clinical settings. Thus, the 3 rd and 4 th experimental conditions both stimulated CIK cell differentiation with 50 ng/ml of anti-CD3 antibody, but with IL-2 concentrations of 500 U/ml and 1000 U/ml, respectively.

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confidence: 91%

“…Acting as an autocrine cytokine, IL-2 plays an important role in the generation and proliferation of effector CIK cells. A great deal of prior research has established that CIK cells secrete IFN-, TNF-, and IL-2 (Hoyle et al, 1998;Kim et al, 2007b;Wang et al, 2008;Zhang et al, 2015).…”

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confidence: 99%

Culture and differentiation of cytokine-induced killer cells from umbilical cord blood-derived mononuclear cells

Duong

et al. 2016

Biomed Res Ther

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“…[10][11][12][13] The antitumor effect of CIK cells was demonstrated particularly in lymphoma cell lines and leukemic blasts, both in vitro and in vivo, [14][15][16] but these cells also have antitumor activity against solid tumors such as osteosarcoma, hepatocellular carcinoma and glioblastoma. [17][18][19] Their cytotoxic effect is mediated by a perforin/granzyme-dependent mechanism. 20,21 Although their tumor recognition and killing properties are not fully understood, these seem to be mediated in part by NKG2D, an activating receptor on NK cells, and the adhesion receptor leukocyte function associated antigen-1 (LFA-1).…”

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confidence: 99%

Efficient lysis of rhabdomyosarcoma cells by cytokine-induced killer cells: implications for adoptive immunotherapy after allogeneic stem cell transplantation

Kuçi¹,

Rettinger²,

Voß³

et al. 2010

Haematologica

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BackgroundRhabdomyosarcoma is the most common soft tissue sarcoma in childhood and has a poor prognosis. Here we assessed the capability of ex vivo expanded cytokine-induced killer cells to lyse both alveolar and embryonic rhabdomyosarcoma cell lines and investigated the mechanisms involved. Design and MethodsPeripheral blood mononuclear cells from six healthy donors were used to generate and expand cytokine-induced killer cells. The phenotype and composition of these cells were determined by multiparameter flow cytometry, while their cytotoxic effect against rhabdomyosarcoma cells was evaluated by a europium release assay. ResultsCytokine-induced killer cells efficiently lysed cells from both rhabdomyosarcoma cell lines. Antibody-mediated masking of either NKG2D molecule on cytokine-induced killer cells or its ligands on rhabdomyosarcoma cells (major histocompatibility antigen related chain A and B and UL16 binding protein 2) diminished this effect by 50%, suggesting a major role for the NKG2D molecule in rhabdomyosarcoma cell killing. No effect was observed after blocking CD11a, CD3 or TCRαb molecules on cytokine-induced killer cells or CD1d on rhabdomyosarcoma cells. Remarkably, cytokine-induced killer cells used tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to activate caspase-3, as the main caspase responsible for the execution of apoptosis. Accordingly, blocking TRAIL receptors on embryonic rhabdomyosarcoma cell lines significantly reduced the anti-tumor effect of cytokine-induced killer cells. About 50% of T cells within the cytokine-induced killer population had an effector memory phenotype, 20% had a naïve phenotype and approximately 30% of the cells had a central memory phenotype. In addition, cytokine-induced killer cells expressed low levels of activation-induced markers CD69 and CD137 and demonstrated a low alloreactive potential. ConclusionsOur data suggest that cytokine-induced killer cells may be used as a novel adoptive immunotherapy for the treatment of patients with rhabdomyosarcoma after allogeneic stem cell transplantation.Key words: CIK, NKG2D, lysis, rhabdomyosarcoma.Citation: Kuçi S, Rettinger E, Voß B, Weber G, Stais M, Kreyenberg H, Willasch A, Kuçi Z, Koscielniak E, Klöss S, von Laer D, Klingebiel T, and Bader P Haematologica 2010;95(9):1579-1586. doi:10.3324/haematol.2009 This is an open-access paper. . Efficient lysis of rhabdomyosarcoma cells by cytokine-induced killer cells: implications for adoptive immunotherapy after allogeneic stem cell transplantation. Efficient lysis of rhabdomyosarcoma cells by cytokine-induced killer cells: implications for adoptive immunotherapy after allogeneic stem cell transplantation

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“…Specific pathogen-free BALB/ c-nu female mice (SLC, Hamamatsu, Japan), 5-weeks old and weighing from 15.5 to 16.5 g, were maintained as previously described (15). All animals were allowed to acclimatize to the local environment for at least 1 week before use.…”

Section: Western Immunoblot Analysismentioning

confidence: 99%

Widdrol induces apoptosis via activation of AMP-activated protein kinase in colon cancer cells

Kang

Park²,

Lee³

et al. 2012

Oncol Rep

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Abstract. Widdrol, a natural sesquiterpene present in Juniperus sp., has been shown to exert anticancer and antifungal effects. Emerging evidence has suggested that AMP-activated protein kinase (AMPK), which functions as a cellular energy sensor, is a potential therapeutic target for human cancers. In this study, we found that AMPK mediates the anticancer effects of widdrol through induction of apoptosis in HT-29 colon cancer cells. We showed that widdrol induced the phosphorylation of AMPK in a dose-and time-dependent manner. The selective AMPK inhibitor compound C abrogated the inhibitory effect of widdrol on HT-29 cell growth. In addition, we demonstrated that widdrol induced apoptosis and this was associated with the activation of caspases, including caspase-3/7 and caspase-9, in HT-29 cells. We also demonstrated that transfection of HT-29 cells with AMPK siRNAs significantly suppressed the widdrol-mediated apoptosis and the activation of caspases. However, cell cycle arrest induced by widdrol was not affected by transfection of HT-29 cells with AMPK siRNAs. Furthermore, widdrol inhibited HT-29 tumor growth in a human tumor xenograft model. Taken together, our results suggest that the anticancer effect of widdrol may be mediated, at least in part, by induction of apoptosis via AMPK activation. IntroductionAMP-activated protein kinase (AMPK), a serine/threonine protein kinase conserved in eukaryotes, is known as a cellular energy sensor involved in the regulation of the response to environmental or nutritional stress (1). AMPK is a heterotrimeric complex composed of catalytic α subunit and regulatory β and γ subunits. AMPK is activated in response to energy deprivation and the activation of AMPK regulates a variety of cellular processes, such as hepatic fatty acid oxidation, lipogenesis, glycogen synthesis and glucose uptake (2). Recently, AMPK has also been identified as a potential target for cancer prevention and/or treatment (3). Indeed, a variety of AMPK activators have been shown to exert anticancer effects (4-6). Especially, metformin, an orally available biguanide derivative that is widely used for the treatment of Type 2 diabetes, was shown to exert anticancer effects by activation of AMPK and is currently being investigated in clinical trials (4). AMPK is also reported to be linked with tumor suppressors, such as liver kinase B1 (LBK1), p21, p53 and tuberous sclerosis complex 2 (TSC2), indicating that AMPK is a potential therapeutic target for cancer (7-9).The leaves of Juniperus chinensis have been reported to contain a lignan with strong anti-leukemic and antitumor activities (10) and a sesquiterpene with anti-fungal activity (11). Widdrol is an odorant derivative contained in various plants of Juniperus sp., including J. chinensis and J. lucayana (12,13). In a previous study, widdrol was shown to induce cell cycle arrest in HT-29 cells (13). To find additional mechanisms involved in the anticancer activity of widdrol, we examined whether widdrol induces apoptosis and characterized molecular mecha...

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Anti-tumor activity of ex vivo expanded cytokine-induced killer cells against human hepatocellular carcinoma

Cited by 42 publications

References 34 publications

Culture and differentiation of cytokine-induced killer cells from umbilical cord blood-derived mononuclear cells

Culture and differentiation of cytokine-induced killer cells from umbilical cord blood-derived mononuclear cells

Efficient lysis of rhabdomyosarcoma cells by cytokine-induced killer cells: implications for adoptive immunotherapy after allogeneic stem cell transplantation

Widdrol induces apoptosis via activation of AMP-activated protein kinase in colon cancer cells

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