Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 44
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Blood ; 143(21): 2152-2165, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38437725

RESUMO

ABSTRACT: Effective T-cell responses not only require the engagement of T-cell receptors (TCRs; "signal 1"), but also the availability of costimulatory signals ("signal 2"). T-cell bispecific antibodies (TCBs) deliver a robust signal 1 by engaging the TCR signaling component CD3ε, while simultaneously binding to tumor antigens. The CD20-TCB glofitamab redirects T cells to CD20-expressing malignant B cells. Although glofitamab exhibits strong single-agent efficacy, adding costimulatory signaling may enhance the depth and durability of T-cell-mediated tumor cell killing. We developed a bispecific CD19-targeted CD28 agonist (CD19-CD28), RG6333, to enhance the efficacy of glofitamab and similar TCBs by delivering signal 2 to tumor-infiltrating T cells. CD19-CD28 distinguishes itself from the superagonistic antibody TGN1412, because its activity requires the simultaneous presence of a TCR signal and CD19 target binding. This is achieved through its engineered format incorporating a mutated Fc region with abolished FcγR and C1q binding, CD28 monovalency, and a moderate CD28 binding affinity. In combination with glofitamab, CD19-CD28 strongly increased T-cell effector functions in ex vivo assays using peripheral blood mononuclear cells and spleen samples derived from patients with lymphoma and enhanced glofitamab-mediated regression of aggressive lymphomas in humanized mice. Notably, the triple combination of glofitamab with CD19-CD28 with the costimulatory 4-1BB agonist, CD19-4-1BBL, offered substantially improved long-term tumor control over glofitamab monotherapy and respective duplet combinations. Our findings highlight CD19-CD28 as a safe and highly efficacious off-the-shelf combination partner for glofitamab, similar TCBs, and other costimulatory agonists. CD19-CD28 is currently in a phase 1 clinical trial in combination with glofitamab. This trial was registered at www.clinicaltrials.gov as #NCT05219513.


Assuntos
Anticorpos Biespecíficos , Antígenos CD19 , Antígenos CD20 , Antígenos CD28 , Imunoterapia , Humanos , Antígenos CD28/imunologia , Antígenos CD28/agonistas , Animais , Camundongos , Anticorpos Biespecíficos/farmacologia , Antígenos CD19/imunologia , Antígenos CD20/imunologia , Imunoterapia/métodos , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos NOD
2.
Front Immunol ; 14: 1211730, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37449203

RESUMO

Intracellular recognition of self and non-self -nucleic acids can result in the initiation of effective pro-inflammatory and anti-tumorigenic responses. We hypothesized that macrophages can be activated by tumor-derived nucleic acids to induce inflammasome activation in the tumor microenvironment. We show that tumor conditioned media (CM) can induce IL-1ß production, indicative of inflammasome activation in primed macrophages. This could be partially dependent on caspase 1/11, AIM2 and NLRP3. IL-1ß enhances tumor cell proliferation, migration and invasion while coculture of tumor cells with macrophages enhances the proliferation of tumor cells, which is AIM2 and caspase 1/11 dependent. Furthermore, we have identified that DNA-RNA hybrids could be the nucleic acid form which activates AIM2 inflammasome at a higher sensitivity as compared to dsDNA. Taken together, the tumor-secretome stimulates an innate immune pathway in macrophages which promotes paracrine cancer growth and may be a key tumorigenic pathway in cancer. Broader understanding on the mechanisms of nucleic acid recognition and interaction with innate immune signaling pathway will help us to better appreciate its potential application in diagnostic and therapeutic benefit in cancer.


Assuntos
Inflamassomos , Neoplasias , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Caspase 1/metabolismo , Microambiente Tumoral , Proteínas de Ligação a DNA/metabolismo , Macrófagos , DNA/metabolismo , Neoplasias/metabolismo , Carcinogênese/metabolismo
3.
J Immunother Cancer ; 10(6)2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35688559

RESUMO

BACKGROUND: Dendritic cells (DCs) are professional antigen presenting cells that initiate immune defense to pathogens and tumor cells. Human tumors contain only few DCs that mostly display a non-activated phenotype. Hence, activation of tumor-associated DCs may improve efficacy of cancer immunotherapies. Toll-like receptor (TLR) agonists and interferons are known to promote DC maturation. However, it is unclear if DCs in human tumors respond to activation signals and which stimuli induce the optimal activation of human tumor DCs. METHODS: We first screened combinations of TLR agonists, a STING agonist and interferons (IFNs) for their ability to activate human conventional DCs (cDCs). Two combinations: TL8-506 (a TLR8 agonist)+IFN-γ and TL8-506+Poly(I:C) (a TLR3 agonist) were studied in more detail. cDC1s and cDC2s derived from cord blood stem cells, blood or patient tumor samples were stimulated with either TL8-506+IFN-γ or TL8-506+Poly(I:C). Different activation markers were analyzed by ELISA, flow cytometry, NanoString nCounter Technology or single-cell RNA-sequencing. T cell activation and migration assays were performed to assess functional consequences of cDC activation. RESULTS: We show that TL8-506 synergized with IFN-γ or Poly(I:C) to induce high expression of different chemokines and cytokines including interleukin (IL)-12p70 in human cord blood and blood cDC subsets in a combination-specific manner. Importantly, both combinations induced the activation of cDC subsets in patient tumor samples ex vivo. The expression of immunostimulatory genes important for anticancer responses including CD40, IFNB1, IFNL1, IL12A and IL12B were upregulated on stimulation. Furthermore, chemokines associated with CD8+ T cell recruitment were induced in tumor-derived cDCs in response to TL8-506 combinations. In vitro activation and migration assays confirmed that stimulated cDCs induce T cell activation and migration. CONCLUSIONS: Our data suggest that cord blood-derived and blood-derived cDCs are a good surrogate to study treatment responses in human tumor cDCs. While most cDCs in human tumors display a non-activated phenotype, TL8-506 combinations drive human tumor cDCs towards an immunostimulatory phenotype associated with Th1 responses on stimulation. Hence, TL8-506-based combinations may be promising candidates to initiate or boost antitumor responses in patients with cancer.


Assuntos
Neoplasias , Receptor 8 Toll-Like , Adjuvantes Imunológicos/farmacologia , Citocinas/metabolismo , Células Dendríticas , Humanos , Interferon gama/metabolismo , Interferon gama/farmacologia , Interleucina-12/metabolismo , Poli I-C/metabolismo , Poli I-C/farmacologia
4.
Cell Death Differ ; 28(11): 3022-3035, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34091599

RESUMO

Dysfunction of adipocytes and adipose tissue is a primary defect in obesity and obesity-associated metabolic diseases. Interferon regulatory factor 3 (IRF3) has been implicated in adipogenesis. However, the role of IRF3 in obesity and obesity-associated disorders remains unclear. Here, we show that IRF3 expression in human adipose tissues is positively associated with insulin sensitivity and negatively associated with type 2 diabetes. In mouse pre-adipocytes, deficiency of IRF3 results in increased expression of PPARγ and PPARγ-mediated adipogenic genes, leading to increased adipogenesis and altered adipocyte functionality. The IRF3 knockout (KO) mice develop obesity, insulin resistance, glucose intolerance, and eventually type 2 diabetes with aging, which is associated with the development of white adipose tissue (WAT) inflammation. Increased macrophage accumulation with M1 phenotype which is due to the loss of IFNß-mediated IL-10 expression is observed in WAT of the KO mice compared to that in wild-type mice. Bone-marrow reconstitution experiments demonstrate that the nonhematopoietic cells are the primary contributors to the development of obesity and both hematopoietic and nonhematopoietic cells contribute to the development of obesity-related complications in IRF3 KO mice. This study demonstrates that IRF3 regulates the biology of multiple cell types including adipocytes and macrophages to prevent the development of obesity and obesity-related complications and hence, could be a potential target for therapeutic interventions for the prevention and treatment of obesity-associated metabolic disorders.


Assuntos
Tecido Adiposo/fisiopatologia , Inflamação/fisiopatologia , Fator Regulador 3 de Interferon/genética , Obesidade/genética , Animais , Diferenciação Celular , Humanos , Masculino , Camundongos
5.
Sci Rep ; 11(1): 7243, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33790360

RESUMO

Deficiencies in DNA repair and DNA degrading nucleases lead to accumulation of cytosolic DNA. cGAS is a critical DNA sensor for the detection of cytosolic DNA and subsequent activation of the STING signaling pathway. Here, we show that the cGAS-STING pathway was unresponsive to STING agonists and failed to induce type I interferon (IFN) expression in many tested human tumor cells including DU145 prostate cancer cells. Inhibition of IL-6 or the downstream JAK2/STAT3 signaling restored responsiveness to STING agonists in DU145 cells. STING activity in murine TRAMP-C2 prostate cancer cells was critical for tumor rejection and immune cell infiltration. Endogenous STING agonists including double-stranded DNA and RNA:DNA hybrids present in TRAMP-C2 cells contribute to tumor rejection, but tumor growth was further suppressed by administration of cGAMP. Intratumoral co-injections of IL-6 significantly reduced the anti-tumor effects of cGAMP. In summary, STING in tumor cells contributes to tumor rejection in prostate cancer cells, but its functions are frequently suppressed in tumor cells in part via JAK2 and STAT3 pathways.


Assuntos
Janus Quinase 2/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias/metabolismo , Nucleotidiltransferases/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Células A549 , Animais , Células HeLa , Humanos , Janus Quinase 2/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Neoplasias/genética , Nucleotidiltransferases/genética , Fator de Transcrição STAT3/genética , Células THP-1
6.
Oncoimmunology ; 10(1): 1869389, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33520408

RESUMO

Based on the success of tumor-infiltrating lymphocytes (TIL)-based therapies, personalized adoptive cell therapies (ACT) targeting neoantigens have the potential to become a disruptive technology and lead to highly effective treatments for cancer patients for whom no other options exist. ACT of TIL, peripheral blood or gene-engineered peripheral blood lymphocytes (PBLs) targeting neoantigens is a highly personalized intervention that requires three discrete steps: i) Identification of suitable personal targets (neoantigens), ii) selection of T cells or their T cell receptors (TCRs) that are specific for the identified neoantigens and iii) expansion of the selected T cell population or generation of sufficient number of TCR modified T cells. In this review, we provide an introduction into challenges and approaches to identify neoantigens and to select the Adoptive Cell Therapy, ACT, Neoantigen, T cell, Cancer respective neoantigen-reactive T cells for use in ACT.


Assuntos
Linfócitos do Interstício Tumoral , Linfócitos T , Antígenos de Neoplasias/genética , Humanos , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/genética
7.
Proc Natl Acad Sci U S A ; 117(27): 15923-15934, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571920

RESUMO

Burkholderia pseudomallei is the causative agent of melioidosis, an infectious disease in the tropics and subtropics with high morbidity and mortality. The facultative intracellular bacterium induces host cell fusion through its type VI secretion system 5 (T6SS5) as an important part of its pathogenesis in mammalian hosts. This allows it to spread intercellularly without encountering extracellular host defenses. We report that bacterial T6SS5-dependent cell fusion triggers type I IFN gene expression in the host and leads to activation of the cGAMP synthase-stimulator of IFN genes (cGAS-STING) pathway, independent of bacterial ligands. Aberrant and abortive mitotic events result in the formation of micronuclei colocalizing with cGAS, which is activated by double-stranded DNA. Surprisingly, cGAS-STING activation leads to type I IFN transcription but not its production. Instead, the activation of cGAS and STING results in autophagic cell death. We also observed type I IFN gene expression, micronuclei formation, and death of chemically induced cell fusions. Therefore, we propose that the cGAS-STING pathway senses unnatural cell fusion through micronuclei formation as a danger signal, and consequently limits aberrant cell division and potential cellular transformation through autophagic death induction.


Assuntos
Proteínas de Membrana/metabolismo , Nucleotidiltransferases/genética , Burkholderia pseudomallei/metabolismo , Fusão Celular , Dano ao DNA , Regulação da Expressão Gênica , Instabilidade Genômica , Células Hep G2 , Humanos , Imunidade Inata , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Proteínas de Membrana/genética , Microscopia Confocal , Nucleotidiltransferases/metabolismo , Transdução de Sinais
8.
Endocr Relat Cancer ; 24(12): T283-T295, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28754821

RESUMO

Recent success in immunomodulating strategies in lung cancer and melanoma has prompted much enthusiasm in their potential to treat other advanced solid malignancies. However, their applications have shown variable success and are even ineffective against some tumours. The efficiency of immunotherapies relies on an immunogenic tumour microenvironment. The current field of cancer immunology has focused on understanding the interaction of cancer and host immune cells to break the state of immune tolerance and explain how molecular patterns of cytokines and chemokines affect tumour progression. Here, we review our current knowledge of how inherent properties of tumours and their different tumour microenvironments affect therapeutic outcome. We also discuss insights into recent multimodal therapeutic approaches that target tumour immune evasion and suppression to restore anti-tumour immunity.


Assuntos
Imunoterapia/métodos , Humanos , Microambiente Tumoral
9.
Mech Ageing Dev ; 165(Pt A): 33-46, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27614000

RESUMO

The presence of damaged and microbial DNA can pose a threat to the survival of organisms. Cells express various sensors that recognize specific aspects of such potentially dangerous DNA. Recognition of damaged or microbial DNA by sensors induces cellular processes that are important for DNA repair and inflammation. Here, we review recent evidence that the cellular response to DNA damage and microbial DNA are tightly intertwined. We also discuss insights into the parameters that enable DNA sensors to distinguish damaged and microbial DNA from DNA present in healthy cells.


Assuntos
Bactérias/imunologia , Reparo do DNA/imunologia , DNA Bacteriano/imunologia , Animais , Bactérias/genética , Reparo do DNA/genética , DNA Bacteriano/genética , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia
10.
Immunity ; 44(5): 1177-89, 2016 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-27178469

RESUMO

Self-DNA is present in the cytosol of many cancer cells and can promote effective immune rejection of tumor cells, but the mechanisms leading to the presence of cytosolic DNA are unknown. Here, we report that the cleavage of genomic DNA by DNA structure-specific endonuclease MUS81 and PARP-dependent DNA repair pathways leads to the accumulation of cytosolic DNA in prostate cancer cells. The number of nuclear MUS81 foci and the amount of cytosolic dsDNA increased in tandem from hyperplasia to clinical stage II prostate cancers and decreased at stage III. Cytosolic DNA generated by MUS81 stimulated DNA sensor STING-dependent type I interferon (IFN) expression and promoted phagocytic and T cell responses, resulting in type I and II IFN-mediated rejection of prostate tumor cells via mechanisms that partly depended on macrophages. Our results demonstrate that the tumor suppressor MUS81 alerts the immune system to the presence of transformed host cells.


Assuntos
Autoantígenos/metabolismo , Proteínas de Ligação a DNA/metabolismo , DNA/metabolismo , Endonucleases/metabolismo , Neoplasias da Próstata/imunologia , Linfócitos T/imunologia , Animais , Autoantígenos/imunologia , Linhagem Celular Tumoral , DNA/imunologia , Humanos , Interferon Tipo I/metabolismo , Ativação Linfocitária , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estadiamento de Neoplasias , Neoplasias Experimentais , Fagocitose , Neoplasias da Próstata/patologia
11.
Cancer Immunol Res ; 4(4): 294-302, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26873573

RESUMO

Apoptosis is a controlled means of eliminating damaged cells without causing an inflammatory response or tissue damage. The mechanisms that contribute to the suppression of an inflammatory response upon apoptosis of cells are poorly understood. Here, we report that apoptotic cells release the interleukin-1 receptor antagonist (IL1RA). The release of IL1RA depended on the DNA damage response, caspase 9, and caspase 3.De novotranslation, classical secretion pathways, or N-glycosylation was not required for the release of IL1RA. The amounts of IL1RA released by apoptotic cells impaired IL1-induced expression of IL6 In summary, we demonstrate that the release of IL1RA in response to genotoxic stress contributes to the immunosuppressive effects of apoptotic cells.


Assuntos
Apoptose/genética , Dano ao DNA , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Animais , Apoptose/imunologia , Bleomicina/farmacologia , Caspases/metabolismo , Linhagem Celular , Fibroblastos , Expressão Gênica , Humanos , Imunomodulação , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1/metabolismo , Macrófagos , Camundongos , Biossíntese de Proteínas , Transdução de Sinais
12.
J Vis Exp ; (107)2016 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-26779653

RESUMO

Primary cells are derived directly from tissue and are thought to be more representative of the physiological state of cells in vivo than established cell lines. However, primary cell cultures usually have a finite life span and need to be frequently re-established. Fibroblasts are an easily accessible source of primary cells. Here, we discuss a simple and quick experimental procedure to establish primary fibroblast cultures from ears and tails of mice. The protocol can be used to establish primary fibroblast cultures from ears stored at RT for up to 10 days. When the protocol is carefully followed, contaminations are unlikely to occur despite the use of non-sterile tissue stored for extended time in some cases. Fibroblasts proliferate rapidly in culture and can be expanded to substantial numbers before undergoing replicative senescence.


Assuntos
Orelha/anatomia & histologia , Fibroblastos/citologia , Cultura Primária de Células/métodos , Cauda/citologia , Animais , Linhagem Celular , Camundongos , Camundongos Endogâmicos C57BL
13.
Cytokine ; 76(2): 581-582, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26070935

RESUMO

We recently provided evidence that genome-derived DNA is present in the cytosol of many tumor cells. Genomic loci that give rise to cytosolic DNA can potentially form non-B DNA structures including triple-stranded RNA:DNA structures (R-loops). The RNA:DNA-specific endonuclease RNaseh1 reduced the levels of cytosolic DNA and type I interferon-dependent rejection of B-cell lymphoma suggesting that cytosolic DNA may contribute to immune surveillance of B-cell lymphoma.


Assuntos
DNA/genética , Genoma , Interferon Tipo I/genética , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Linhagem Celular Tumoral , Humanos , RNA/genética
14.
Cell Rep ; 11(3): 460-73, 2015 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-25865892

RESUMO

The DNA damage response (DDR) induces the expression of type I interferons (IFNs), but the underlying mechanisms are poorly understood. Here, we show the presence of cytosolic DNA in different mouse and human tumor cells. Treatment of cells with genotoxic agents increased the levels of cytosolic DNA in a DDR-dependent manner. Cloning of cytosolic DNA molecules from mouse lymphoma cells suggests that cytosolic DNA is derived from unique genomic loci and has the potential to form non-B DNA structures, including R-loops. Overexpression of Rnaseh1, which resolves R-loops, reduced the levels of cytosolic DNA, type I Ifn transcripts, and type I IFN-dependent rejection of lymphoma cells. Live-cell imaging showed a dynamic contact of cytosolic DNA with mitochondria, an important organelle for innate immune recognition of cytosolic nucleotides. In summary, we found that cytosolic DNA is present in many tumor cells and contributes to the immunogenicity of tumor cells.


Assuntos
DNA/imunologia , Interferon Tipo I/imunologia , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Transferência Adotiva , Animais , Linhagem Celular , Citosol/imunologia , Citosol/metabolismo , Dano ao DNA/imunologia , Células HCT116 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Reação em Cadeia da Polimerase em Tempo Real
15.
J Biol Chem ; 290(12): 7463-73, 2015 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-25623070

RESUMO

RNA:DNA hybrids form in the nuclei and mitochondria of cells as transcription-induced R-loops or G-quadruplexes, but exist only in the cytosol of virus-infected cells. Little is known about the existence of RNA:DNA hybrids in the cytosol of virus-free cells, in particular cancer or transformed cells. Here, we show that cytosolic RNA:DNA hybrids are present in various human cell lines, including transformed cells. Inhibition of RNA polymerase III (Pol III), but not DNA polymerase, abrogated cytosolic RNA:DNA hybrids. Cytosolic RNA:DNA hybrids bind to several components of the microRNA (miRNA) machinery-related proteins, including AGO2 and DDX17. Furthermore, we identified miRNAs that are specifically regulated by Pol III, providing a potential link between RNA:DNA hybrids and the miRNA machinery. One of the target genes, exportin-1, is shown to regulate cytosolic RNA:DNA hybrids. Taken together, we reveal previously unknown mechanism by which Pol III regulates the presence of cytosolic RNA:DNA hybrids and miRNA biogenesis in various human cells.


Assuntos
DNA/genética , MicroRNAs/genética , Hibridização de Ácido Nucleico , RNA Polimerase III/metabolismo , RNA/genética , Sequência de Bases , Linhagem Celular Tumoral , Citosol/metabolismo , Dano ao DNA , Humanos , Espectrometria de Massas , Análise de Sequência com Séries de Oligonucleotídeos , RNA Interferente Pequeno
16.
Oncoimmunology ; 3: e29259, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25114832

RESUMO

The DNA damage response (DDR) upregulates the expression of NKG2D ligands (NKG2DLs).1,2 We have recently reported that the DDR also induces the presence of cytosolic DNA in B-cell lymphoma cells, which leads to the activation of STING-dependent cytosolic DNA sensor pathways and the expression of RAE-1 ligands for NKG2D.3.

17.
Clin Cancer Res ; 20(13): 3485-95, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24799523

RESUMO

PURPOSE: The low immunogenicity of many cancer cells and the immunosuppression by various cancers and anticancer therapies have been an obstacle in the development of efficacious immunotherapies. Our goal was to test whether Toll-like receptor (TLR) agonists and anticancer chemotherapeutic agents synergize in rendering tumor cells more immunogenic. EXPERIMENTAL DESIGN: We treated B-cell lymphoma cells with the TLR1/2 agonist Pam3CSK4 and the genotoxic anticancer agent 1-ß-D-arabinofuranosylcytosine (Ara-C). The effects on the immunogenicity of tumor cells were measured in transfer experiments and in vitro studies. RESULTS: The treatment of B-cell lymphoma cells with the TLR1/2 agonist Pam3CSK4 enhanced the anticancer effects of the genotoxic agent Ara-C. Mice injected with cotreated tumor cells survived longer than mice challenged with Pam3CSK4 or Ara-C-treated cells. Administration of Pam3CSK4 or Ara-C reduced the tumor load of mice injected with tumor cells. Cotreatment had no effect on the rate of apoptosis or proliferation of Ara-C-treated cells, but upregulated the expression of several immunomodulatory molecules. Consistent with an increased immunogenicity of Pam3CSK4 and Ara-C-treated B-cell lymphoma cells, rejection of cotreated tumor cells required natural killer cells and T cells. We demonstrate that the upregulation of immunomodulatory molecules in response to Pam3CSK4 and Ara-C depended in part on NF-κB. CONCLUSION: TLR agonists can increase the efficacy of conventional cancer therapies by altering the immunogenicity of B-cell lymphoma cells.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Citarabina/farmacologia , Lipopeptídeos/farmacologia , Linfoma de Células B/metabolismo , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Análise por Conglomerados , Citarabina/administração & dosagem , Modelos Animais de Doenças , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Perfilação da Expressão Gênica , Imunomodulação/efeitos dos fármacos , Imunomodulação/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Lipopeptídeos/administração & dosagem , Células Progenitoras Linfoides/efeitos dos fármacos , Células Progenitoras Linfoides/metabolismo , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Linfoma de Células B/mortalidade , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Receptor 2 Toll-Like/agonistas
18.
Cancer Res ; 74(8): 2193-2203, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24590060

RESUMO

The immunoreceptor NKG2D originally identified in natural killer (NK) cells recognizes ligands that are upregulated on tumor cells. Expression of NKG2D ligands (NKG2DL) is induced by the DNA damage response (DDR), which is often activated constitutively in cancer cells, revealing them to NK cells as a mechanism of immunosurveillance. Here, we report that the induction of retinoic acid early transcript 1 (RAE1) ligands for NKG2D by the DDR relies on a STING-dependent DNA sensor pathway involving the effector molecules TBK1 and IRF3. Cytosolic DNA was detected in lymphoma cell lines that express RAE1 and its occurrence required activation of the DDR. Transfection of DNA into ligand-negative cells was sufficient to induce RAE1 expression. Irf3(+/-);Eµ-Myc mice expressed lower levels of RAE1 on tumor cells and showed a reduced survival rate compared with Irf3(+/+);Eµ-Myc mice. Taken together, our results suggest that genomic damage in tumor cells leads to activation of STING-dependent DNA sensor pathways, thereby activating RAE1 and enabling tumor immunosurveillance.


Assuntos
Dano ao DNA/genética , Dano ao DNA/fisiologia , DNA de Neoplasias/metabolismo , Linfoma/metabolismo , Proteínas de Membrana/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Proteínas Associadas à Matriz Nuclear/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Animais , Linhagem Celular Tumoral , Dano ao DNA/efeitos da radiação , Vigilância Imunológica , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/imunologia , Fator Regulador 3 de Interferon/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ligantes , Linfoma/genética , Linfoma/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Proteínas Associadas à Matriz Nuclear/biossíntese , Proteínas Associadas à Matriz Nuclear/genética , Proteínas Associadas à Matriz Nuclear/imunologia , Proteínas de Transporte Nucleocitoplasmático/biossíntese , Proteínas de Transporte Nucleocitoplasmático/genética , Proteínas de Transporte Nucleocitoplasmático/imunologia , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Transfecção , Regulação para Cima
19.
Immunol Cell Biol ; 92(3): 230-6, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24445601

RESUMO

The natural killer (NK) group 2 member D (NKG2D) is an activating immune receptor expressed on NK cells, cytotoxic T cells and a subset of other T cells. It has an important role in the recognition and lysis of a variety of infected and tumor cells. Despite significant gains in our understanding of NKG2D, the relevance of NKG2D and its ligands in human diseases has only recently started to emerge. Here, we present an overview of the recent advances in NKG2D biology, discuss the expression of NKG2D ligands in cancer patients and evaluate the diagnostic and prognostic potential of NKG2D ligands.


Assuntos
Células Matadoras Naturais/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Animais , Linhagem Celular Tumoral , Humanos , Ligantes , Neoplasias/imunologia , Neoplasias/patologia , Solubilidade
20.
Eur J Immunol ; 44(4): 1108-18, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24375454

RESUMO

The DNA damage response (DDR) alerts the immune system to the danger posed by DNA damage through the induction of damage-associated molecular pattern molecules, chemokines, and ligands for activating immune receptors such as lymphocyte function-associated antigen 1 (LFA-1), NKG2D, and DNAX accessory molecule 1 (DNAM-1). Here we provide evidence that OVA(257-264) -pulsed fibroblasts gain the ability to activate naïve OT-I CD8(+) T cells in response to DNA damage. The ability of fibroblasts to activate OT-I CD8(+) T cells depended on the upregulation of ICAM-1 on fibroblasts and DNAM-1 expression of CD8(+) T cells. OVA(257-264) -pulsed fibroblasts were able to induce a protective T-cell response against B16-OVA cells in a DDR-dependent manner. Hence, the DDR may alert the immune system to the presence of potentially dangerous cells by upregulating the expression of ligands that can induce the activation of innate and adaptive immune cells.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Dano ao DNA/imunologia , Fibroblastos/imunologia , Animais , Células Apresentadoras de Antígenos/metabolismo , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos de Diferenciação de Linfócitos T/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/imunologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Benzenoacetamidas/imunologia , Benzenoacetamidas/farmacologia , Western Blotting , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Técnicas de Cocultura , Citarabina/imunologia , Citarabina/farmacologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Citometria de Fluxo , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Ovalbumina/genética , Ovalbumina/imunologia , Ovalbumina/metabolismo , Tioureia/análogos & derivados , Tioureia/imunologia , Tioureia/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...