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1.
Front Genet ; 6: 11, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25699074

RESUMO

Chronic lymphocytic leukemia (CLL) is the most prominent B cell malignancy among adults in the Western world and characterized by a clonal expansion of B cells. The patients suffer from severe immune defects resulting in increased susceptibility to infections and failure to generate an antitumor immune response. Defects in both, DNA damage response (DDR) pathway and crosstalk with the tissue microenvironment have been reported to play a crucial role for the survival of CLL cells, therapy resistance and impaired immune response. To this end, major advances over the past years have highlighted several T cell immune evasion mechanisms in CLL. Here, we discuss the consequences of an impaired DDR pathway for detection and elimination of CLL cells by natural killer (NK) cells. NK cells are considered to be a major component of the immunosurveillance in leukemia but NK cell activity is impaired in CLL. Restoration of NK cell activity using immunoligands and immunoconstructs in combination with the conventional chemotherapy may provide a future perspective for CLL treatment.

2.
Int J Cancer ; 134(12): 2829-40, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24242212

RESUMO

NKG2D, an activating receptor expressed on NK cells and T cells, is critically involved in tumor immunosurveillance. In this study, we explored the potential therapeutic utility of the NKG2D ligand ULBP2 for the treatment of colon carcinoma. To this end we designed a fusion protein consisting of human ULBP2 and an antibody-derived single chain targeting the tumor carcinoembryonic antigen (CEA). The bispecific recombinant fusion protein re-directed NK cells towards malignant cells by binding to both, tumor cells and NK cells, and triggered NK cell-mediated target cell killing in vitro. Moreover, tumor growth was significantly delayed in a syngeneic colon carcinoma mouse model in response to immunoligand treatment. The anti-tumor activity could be attributed to the stimulation of immune cells with an elevated expression of the activation marker CD69 on NK, T and NKT cells and the infiltration of CD45+ immune cells into the solid tumor. In summary, it was demonstrated that immunoligands provide specific tumor targeting by NK cells and exert anti-tumor activity in vitro and in vivo. This technology represents a novel immunotherapeutic strategy for solid tumors with the potential to be further developed for clinical applications.


Assuntos
Antígeno Carcinoembrionário/imunologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/terapia , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Células T Matadoras Naturais/imunologia , Transferência Adotiva , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Antígeno Carcinoembrionário/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Proteínas Ligadas por GPI/uso terapêutico , Células HEK293 , Humanos , Imunoterapia Adotiva , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/transplante , Lectinas Tipo C/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes de Fusão/uso terapêutico , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/imunologia
3.
PLoS One ; 8(11): e79502, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24278143

RESUMO

Epigenetic changes have been implicated in the malignant phenotype of Hodgkin Reed Sternberg (HRS) cells in Hodgkin lymphoma (HL), where HRS survival and proliferation depends on the microenvironment. The histone-deacetylase (HDAC) inhibitor LBH589 (panobinostat) showed clinical efficacy but its impact on the HRS microenvironment is unclear. Hence, we analysed the effects of LBH589 on lymphocytes and also potential combination therapies. In lymphocyte-target cell killing assays, LBH589-treatment triggered an enhanced lymphocyte-dependent lysis of HL cells despite of mild lymphocytopenic effects. In co-culture experiments of lymphocytes with HL cells, LBH589 suppressed the IFNgamma-release but increased the TNFalpha secretion. Recombinant TNFalpha boosted the lymphocyte-dependent lysis of HL target cells. In HL cell lines, LBH589 induced cell death, autophagy, and an increase of MICA/B that are ligands to natural killer cell receptors. The combination of LBH589 with Brentuximab Vedotin was inefficient due to down-regulation of CD30 as a target. Combination with gemcitabine revealed highly significant effects, suggesting a potential combination for future therapy. Based on these data we suggest that LBH589 favourably modulates the cytokine network and lymphocyte activity in the HL microenvironment.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Doença de Hodgkin/metabolismo , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Apoptose/efeitos dos fármacos , Western Blotting , Brentuximab Vedotin , Linhagem Celular Tumoral , Células Cultivadas , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Imunoconjugados/farmacologia , Interferon gama/metabolismo , Antígeno Ki-1/metabolismo , Microscopia de Fluorescência , Panobinostat , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/metabolismo , Gencitabina
4.
Biol Chem ; 394(10): 1325-31, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23787466

RESUMO

Evasion of apoptosis is a hallmark of cancer cells. Inhibitor of apoptosis proteins (IAPs) act as endogenous inhibitors of programmed cell death and are overexpressed in several tumors including Hodgkin lymphoma (HL). Preclinical studies indicate antitumor activity of IAP antagonists and clinical studies in hematological malignancies are underway. Here, we investigate the impact of the small molecule IAP antagonist LCL161 on HL cell lines. Although the antagonist caused rapid degradation of cIAP1 leading to TNFα secretion, LCL161 did not promote apoptosis significantly. However, LCL161 induced expression of MICA and MICB, ligands for the activating immune receptor NKG2D, and enhanced the susceptibility of HL cells to NKG2D-dependent lysis by NK cells. MICA/B upregulation was dependent on activation of the DNA damage response upon LCL161 treatment. Taken together, we demonstrate a novel link between IAP inhibition, DNA damage and immune recognition.


Assuntos
Dano ao DNA/imunologia , Doença de Hodgkin/fisiopatologia , Imunidade Inata/imunologia , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Subfamília K de Receptores Semelhantes a Lectina de Células NK/agonistas , Tiazóis/farmacologia , Regulação para Cima , Western Blotting , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Doença de Hodgkin/imunologia , Humanos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
Ann Med ; 45(4): 384-94, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23701136

RESUMO

Natural killer (NK) cells are able to lyse infected and tumor cells while sparing healthy cells. Recognition of diseased cells by NK cells is governed by several activating and inhibitory receptors. We review numerous pathways that have been implicated in the regulation of self-ligands for activating receptors, including NKG2D, DNAM-1, LFA-1, NKp30, NKp44, NKp46, NKp65, and NKp80 found on NK cells and some T cells. Understanding how the regulation of self-encoded ligand expression is regulated may provide novel avenues for future therapeutic approaches to infections and cancer.


Assuntos
Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Receptores de Células Matadoras Naturais/imunologia , Receptores de Células Matadoras Naturais/metabolismo , Citotoxicidade Imunológica/imunologia , Humanos , Ligantes
6.
Mol Ther ; 21(4): 895-903, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23459515

RESUMO

Natural killer (NK) cells represent a key component of the innate immune system against cancer. Nevertheless, malignant diseases arise in immunocompetent individuals despite tumor immunosurveillance. Hodgkin lymphoma (HL) is characterized by CD30(+) tumor cells and a massive infiltration of immune effector cells in affected lymph nodes. The latter obviously fail to eliminate the malignant cell population. Here, we tested for functional NK cell defects in HL and suggest an improvement of NK function by therapeutic means. We demonstrate that peripheral NK cells (pNK) from patients with HL fail to eliminate HL cell lines in ex vivo killing assays. Impaired NK cell function correlated with elevated serum levels of soluble ligands for NK cell receptors NKp30 (BAG6/BAT3) and NKG2D (MICA), factors known to constrict NK cell function. In vitro, NK cell cytotoxicity could be restored by an NKG2D/NKp30-independent bispecific antibody construct (CD30xCD16A). It artificially links the tumor receptor CD30 with the cytotoxicity NK cell receptor CD16A. Moreover, we observed that NK cells from patients treated with this construct were generally activated and displayed a restored cytotoxicity against HL target cells. These data suggest that reversible suppression of NK cell activity contributes to immune evasion in HL and can be antagonized therapeutically.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Doença de Hodgkin/terapia , Células Matadoras Naturais/imunologia , Anticorpos Biespecíficos/farmacologia , Linhagem Celular Tumoral , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Imuno-Histoquímica
7.
Blood ; 121(18): 3658-65, 2013 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-23509156

RESUMO

Natural killer (NK) cells are a major component of the anti-tumor immune response. NK cell dysfunctions have been reported in various hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here we investigated the role of tumor cell-released soluble and exosomal ligands for NK cell receptors that modulate NK cell activity. Soluble CLL plasma factors suppressed NK cell cytotoxicity and down-regulated the surface receptors CD16 and CD56 on NK cells of healthy donors. The inhibition of NK cell cytotoxicity was attributed to the soluble ligand BAG6/BAT3 that engages the activating receptor NKp30 expressed on NK cells. Soluble BAG6 was detectable in the plasma of CLL patients, with the highest levels at the advanced disease stages. In contrast, NK cells were activated when BAG6 was presented on the surface of exosomes. The latter form was induced in non-CLL cells by cellular stress via an nSmase2-dependent pathway. Such cells were eliminated by lymphocytes in a xenograft tumor model in vivo. Here, exosomal BAG6 was essential for tumor cell killing because BAG6-deficient cells evaded immune detection. Taken together, the findings show that the dysregulated balance of exosomal vs soluble BAG6 expression may cause immune evasion of CLL cells.


Assuntos
Células Matadoras Naturais/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Chaperonas Moleculares/farmacologia , Receptores de Células Matadoras Naturais/metabolismo , Evasão Tumoral/efeitos dos fármacos , Animais , Antígeno CD56/metabolismo , Antígeno CD56/fisiologia , Células Cultivadas , Exossomos/metabolismo , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/fisiologia , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Ligantes , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos SCID , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Receptores de IgG/metabolismo , Receptores de IgG/fisiologia , Receptores de Células Matadoras Naturais/agonistas , Receptores de Células Matadoras Naturais/antagonistas & inibidores , Solubilidade , Evasão Tumoral/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
8.
Am J Hematol ; 88(2): 113-5, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23225085

RESUMO

Hodgkin lymphoma (HL) has become one of the best curable cancers. However, better biomarkers are needed for outcome prediction that would allow protecting patients from over- or under-dosing of treatment. Thymus and activation-regulated chemokine/CCL17 (TARC) is highly and specifically elevated in this disease and has been proposed as possible biomarker in HL patients. In this study, we show that pretreatment TARC levels were associated with established clinical risk factors and predictive for response to treatment in a large cohort of HL patients treated in clinical trials by the German Hodgkin Study Group. Moreover, TARC levels also significantly contributed to a novel multivariate model predicting treatment response. These data clearly suggest an important role for this chemokine as biomarker in HL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiocina CCL17/sangue , Doença de Hodgkin/sangue , Doença de Hodgkin/tratamento farmacológico , Adulto , Biomarcadores/sangue , Estudos de Coortes , Feminino , Alemanha , Doença de Hodgkin/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
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