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1.
J Surg Res ; 245: 552-563, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31472311

RESUMO

BACKGROUND: It is elusive which subtypes of immune cells are pivotal in cancer progression and prognosis in gastric cancer (GC). The aim of this study is to clarify clinical impact of immature myeloid-derived immune cells in patients with GC who underwent curative gastrectomy with curative lymphadenectomy and treated with S-1 (tegafur/gimeracil/oteracil) postoperatively. METHODS: The prognostic impact of recruited CD33+ immature myeloid-derived cells were clinicopathologically analyzed in curatively resected stage II and III GC. Correlation of preoperative peripheral leukocyte fractions with recruited CD33+ immature cells was also assessed. RESULTS: Patients with high CD33+ cell counts in primary tumor showed dramatically worse prognosis (5-y recurrence-free survival 29.0%) than that of the counterparts (79.4%). High CD33+ cell counts independently predicted poor prognosis in stage II/III (hazard ratio, 4.34; P < 0.001). In analyses of each stage, high CD33+ cell count was pivotally associated with poor prognosis in both stages. There was no significant correlation of each peripheral leukocyte fraction with CD33+ cell recruitment. Of note, high CD33+ cell count was significantly correlated with hematogenous recurrence. CONCLUSIONS: Recruitment of CD33+ immature myeloid cells critically predict hematogenous recurrences in curatively resected advanced GC. These results give rational to focusing on CD33+ myeloid-derived cells as a novel approach to tackle advanced GC.


Assuntos
Células Supressoras Mieloides/imunologia , Recidiva Local de Neoplasia/diagnóstico , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Neoplasias Gástricas/terapia , Estômago/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Gastrectomia , Humanos , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Células Supressoras Mieloides/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/imunologia , Estadiamento de Neoplasias , Ácido Oxônico/administração & dosagem , Prognóstico , Estômago/citologia , Estômago/cirurgia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Tegafur/administração & dosagem
2.
Gen Physiol Biophys ; 38(5): 369-378, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31411573

RESUMO

CD33 is a myeloid-associated marker and belongs to the sialic acid-binding immunoglobulin (Ig)-like lectin (Siglec) family. Such types of receptors are highly expressed in acute myeloid leukemia, which could be used in its treatment. CD33 shows high variability in its expression levels with still unknown reasons. Here, we investigated the CD33 expression of monocytes in human blood samples processed at different temperatures and in dependence on their phagocytic activity against opsonized Escherichia coli. The samples were stained by fluorescently labelled anti-human CD14 to specify the monocyte population, anti-human CD33 antibodies to evaluate CD33 expression and analyzed by flow cytometry and confocal laser scanning microscopy. In blood samples kept at 37°C or first pre-chilled at 0°C with subsequent warming up to 37°C, the percentage of CD33-positive monocytes as well as their relative fluorescence intensity was up-regulated compared to samples kept constantly at 0°C. After exposure to E. coli the CD33 relative fluorescence intensity of the monocytes activated at 37°C was 3 to 4 times higher than that of those cells kept inactive at 0°C. Microscopic analysis showed internalisation of CD33 due to its enhanced expression on the surface followed by engulfment of E. coli.


Assuntos
Monócitos/imunologia , Monócitos/metabolismo , Fagocitose , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Temperatura , Escherichia coli/imunologia , Humanos , Receptores de Lipopolissacarídeos/metabolismo , Monócitos/citologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/análise
3.
Int J Pharm ; 568: 118518, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31319147

RESUMO

Most antibody-based therapies for AML target a single antigen on the surface of AML cells, which has a limited clinical benefit due to unsatisfied targeting ability and antigen-negative escape. Here we described the development and specific targeting of daunorubicin (DNR)-loaded CD123/CD33 dual-antibody modified liposome, CD123/CD33-LP-DNR. Since the majority of AML cells carries at least one of the antigens of CD123 and CD33, it is promising to treat AML using the dual-targeting agents. In this study, antibody mixture of CD123 and CD33 (1:1, molar ratio) were thiolated and coupled to Mal-PEG2000-DSPE, then the antibody-Mal-PEG2000-DSPE conjugations were inserted on the DNR-loaded PEGylated liposomes (PEG-LP-DNR) via a post insertion method to prepare CD123/CD33-LP-DNR (antibody/S100PC, molar ratio, 0.06%). The cellular uptake and cytotoxicity were evaluated in THP-1 (CD123brightCD33bright) and HL-60 (CD123dimCD33bright) cells. Compared to the unmodified liposome, CD123/CD33-LP-DNR showed higher cellular uptake which was 1.8-times and 1.6-times in both THP-1 and HL-60 cells, respectively, while the cellular uptake increased to 1.5-times only in the CD123bright cells for the single-antibody modified liposome, CD123-LP-DNR. MTT assay indicated stronger cytotoxicity of CD123/CD33-LP-DNR than CD123-LP-DNR on AML cells. The results indicated that CD123/CD33-LP-DNR might present an effective delivery strategy to enhance the targeting ability against AML cells and potentially reduce the antigen-negative escape.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Daunorrubicina/administração & dosagem , Subunidade alfa de Receptor de Interleucina-3 , Leucemia Mieloide Aguda/tratamento farmacológico , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico , Antibióticos Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Daunorrubicina/química , Liberação Controlada de Fármacos , Células HL-60 , Humanos , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Lipossomos , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Células THP-1 , Evasão Tumoral
4.
Mol Cell Biol ; 39(18)2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31208978

RESUMO

A single nucleotide polymorphism (SNP) in exon 2 of the CD33 gene is associated with reduced susceptibility to late-onset Alzheimer's disease (AD) and causal for elevated mRNA lacking exon 2. In contrast to full-length CD33, transcripts lacking exon 2 result in CD33 protein unable to suppress activation responses in myeloid cells, including microglia. Currently, little is known about the regulation of CD33 exon 2 splicing. Using functional genomics and proteomic approaches, we found that SRSF1 and PTBP1 act as splicing enhancers to increase CD33 exon 2 inclusion in mRNA. Binding of PTBP1 to RNA sequences proximal to the intron 1-exon 2 splice junction is altered by the SNP and represents a potential mechanism behind the SNP-genotype dependent alternative splicing. Our studies also reveal that binding of SRSF1 to the CD33 RNA is not altered by the SNP genotype. Instead, a putative SRSF1 binding sequence at the 3' end of exon 2 directs CD33 exon 2 inclusion into the mRNA, indicating that PTBP1 and SRSF1 promote full-length isoform expression through different mechanisms. Our findings shed light on molecular interactions that regulate CD33 exon 2 splicing, ultimately impacting receptor expression on the cell surface. These data aid in the understanding of CD33's regulation of microglial signaling underpinning the AD genetic associations.


Assuntos
Doença de Alzheimer/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Polimorfismo de Nucleotídeo Único , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Fatores de Processamento de Serina-Arginina/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Idade de Início , Processamento Alternativo , Doença de Alzheimer/metabolismo , Sítios de Ligação , Éxons , Predisposição Genética para Doença , Células HeLa , Humanos , Células K562 , Proteômica/métodos , RNA Mensageiro/química , RNA Mensageiro/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/química , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Células THP-1
5.
Nat Commun ; 10(1): 2759, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227717

RESUMO

Langerhans cells (LC) are thought to be the only mononuclear phagocyte population in the epidermis where they detect pathogens. Here, we show that CD11c+ dendritic cells (DCs) are also present. These cells are transcriptionally similar to dermal cDC2 but are more efficient antigen-presenting cells. Compared to LCs, epidermal CD11c+ DCs are enriched in anogenital tissues where they preferentially interact with HIV, express the higher levels of HIV entry receptor CCR5, support the higher levels of HIV uptake and replication and are more efficient at transmitting the virus to CD4 T cells. Importantly, these findings are observed using both a lab-adapted and transmitted/founder strain of HIV. We also describe a CD33low cell population, which is transcriptionally similar to LCs but does not appear to function as antigen-presenting cells or acts as HIV target cells. Our findings reveal that epidermal DCs in anogenital tissues potentially play a key role in sexual transmission of HIV.


Assuntos
Células Dendríticas/virologia , Células Epidérmicas/virologia , Infecções por HIV/transmissão , HIV-1/imunologia , Apresentação do Antígeno/imunologia , Antígeno CD11c/metabolismo , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Epidérmicas/imunologia , Células Epidérmicas/metabolismo , Epiderme/imunologia , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/patogenicidade , Voluntários Saudáveis , Humanos , Masculino , Cultura Primária de Células , Receptores CCR5/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Linfócitos T/imunologia , Internalização do Vírus
6.
J Immunol Res ; 2019: 6032141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31143782

RESUMO

CD33 (siglec-3), a well-known target in leukemia therapy, is an inhibitory sialoadhesin expressed in human leukocytes of the myeloid lineage and some lymphoid subsets, including NK cells. It may constitute a control mechanism of the innate immune system; nevertheless, its role as an inhibitory receptor remains elusive. Using human NK cells as a cellular model, we analyzed CD33 inhibitory function upon different activating receptors. In high-cytotoxicity NKL cells, CD33 displayed a prominent inhibition on cytotoxicity triggered by the activating receptors NKG2D and, in a lower extent, 2B4, whereas it did not inhibit NKp46-induced cytotoxicity. NKp46 was partially inhibited by CD33 only when low-cytotoxicity NKL cells were tested. CD33 triggering did not inhibit IFN-γ secretion, contrasting with ILT-2 and CD94/NKG2A inhibitory receptors that inhibited cytotoxicity and IFN-γ secretion induced by all activating receptors tested. CD33-mediated inhibition of NKG2D-induced triggering involved Vav1 dephosphorylation. Our results support the role of CD33 as an inhibitory receptor preferentially regulating the NKG2D/DAP10 cytotoxic signaling pathway, which could be involved in self-tolerance and tumor and infected cell recognition.


Assuntos
/imunologia , Células Matadoras Naturais/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Neoplasias/imunologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Citotoxicidade Imunológica , Humanos , Células K562 , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-vav/metabolismo , Receptores Imunológicos/metabolismo , Tolerância a Antígenos Próprios , Transdução de Sinais
7.
Cancer Immunol Immunother ; 68(6): 937-949, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30953118

RESUMO

Gliomas appear to be highly immunosuppressive tumors, with a strong myeloid component. This includes MDSCs, which are a heterogeneous, immature myeloid cell population expressing myeloid markers Siglec-3 (CD33) and CD11b and lacking markers of mature myeloid cells including MHC II. Siglec-3 is a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family and has been suggested to promote MDSC expansion and suppression. Siglecs form a recently defined family of receptors with potential immunoregulatory functions but only limited insight in their expression on immune regulatory cell subsets, prompting us to investigate Siglec expression on MDSCs. We determined the expression of different Siglec family members on monocytic-MDSCs (M-MDSCs) and polymorphnuclear-MDSCs (PMN-MDSCs) from blood of glioma patients and healthy donors, as well as from patient-derived tumor material. Furthermore, we investigated the presence of sialic acid ligands for these Siglecs on MDSCs and in the glioma tumor microenvironment. Both MDSC subsets express Siglec-3, -5, -7 and -9, with higher levels of Siglec-3, -7 and -9 on M-MDSCs and higher Siglec-5 levels on PMN-MDSCs. Similar Siglec expression profiles were found on MDSCs from healthy donors. Furthermore, the presence of Siglec-5 and -9 was also confirmed on PMN-MDSCs from glioma tissue. Interestingly, freshly isolated glioma cells predominantly expressed sialic acid ligands for Siglec-7 and -9, which was confirmed in situ. In conclusion, our data show a distinct Siglec expression profile for M- and PMN-MDSCs and propose possible sialic acid-Siglec interactions between glioma cells and MDSCs in the tumor microenvironment.


Assuntos
Neoplasias Encefálicas/imunologia , Glioma/imunologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/imunologia , Transcriptoma/imunologia , Adulto , Idoso , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Feminino , Glioma/genética , Glioma/terapia , Humanos , Ligantes , Masculino , Pessoa de Meia-Idade , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Isoformas de Proteínas/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/genética , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
8.
Neurobiol Dis ; 127: 432-448, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30951849

RESUMO

Alzheimer's disease (AD) genetics implies a causal role for innate immune genes, TREM2 and CD33, products that oppose each other in the downstream Syk tyrosine kinase pathway, activating microglial phagocytosis of amyloid (Aß). We report effects of low (Curc-lo) and high (Curc-hi) doses of curcumin on neuroinflammation in APPsw transgenic mice. Results showed that Curc-lo decreased CD33 and increased TREM2 expression (predicted to decrease AD risk) and also increased TyroBP, which controls a neuroinflammatory gene network implicated in AD as well as phagocytosis markers CD68 and Arg1. Curc-lo coordinately restored tightly correlated relationships between these genes' expression levels, and decreased expression of genes characteristic of toxic pro-inflammatory M1 microglia (CD11b, iNOS, COX-2, IL1ß). In contrast, very high dose curcumin did not show these effects, failed to clear amyloid plaques, and dysregulated gene expression relationships. Curc-lo stimulated microglial migration to and phagocytosis of amyloid plaques both in vivo and in ex vivo assays of sections of human AD brain and of mouse brain. Curcumin also reduced levels of miR-155, a micro-RNA reported to drive a neurodegenerative microglial phenotype. In conditions without amyloid (human microglial cells in vitro, aged wild-type mice), Curc-lo similarly decreased CD33 and increased TREM2. Like curcumin, anti-Aß antibody (also reported to engage the Syk pathway, increase CD68, and decrease amyloid burden in human and mouse brain) increased TREM2 in APPsw mice and decreased amyloid in human AD sections ex vivo. We conclude that curcumin is an immunomodulatory treatment capable of emulating anti-Aß vaccine in stimulating phagocytic clearance of amyloid by reducing CD33 and increasing TREM2 and TyroBP, while restoring neuroinflammatory networks implicated in neurodegenerative diseases.


Assuntos
Doença de Alzheimer/genética , Anti-Inflamatórios não Esteroides/farmacologia , Encéfalo/efeitos dos fármacos , Curcumina/farmacologia , Expressão Gênica/efeitos dos fármacos , Imunidade Inata/genética , Microglia/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Fagocitose/efeitos dos fármacos , Placa Amiloide/genética , Placa Amiloide/metabolismo , Receptores Imunológicos/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo
9.
Biomater Sci ; 7(3): 938-950, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30519686

RESUMO

Aptamers are short single-stranded DNA or RNA molecules, which have recently been developed for potential broad applications such as clinical therapeutics, diagnosis and tumor-targeted drug delivery. However, the selection of specific aptamers is often unsatisfactory using the classical protein or cell-based SELEX. Herein, we modified the paired cell line approach to identify aptamers targeting leukemia cells expressing the CD33 antigen. Our strategy artfully used the same cells for negative (HEK293T cells) and positive (CD33 transfected-HEK293T cells) aptamer selections, and the negative selections were performed adequately before the positive selection to remove unspecific sequences. The advantages of this strategy are that it is fast and accurate, where only a few rounds of selection together with PCR amplifications are sufficient to obtain high binding affinity antigen-targeted aptamers. By using our modified approach, we successfully obtained the CD33-targeting aptamer S30, which could highly recognize the C2 domain of the CD33 antigen in vitro and in vivo. Moreover, the optimized aptamer S30-T1 (i.e., core region of S30) was conjugated with doxorubicin (Dox) to synthesize S30-T1-Dox conjugates, which could specifically inhibit CD33 positive acute myeloid leukemia HL-60 cell proliferation by arresting the cell cycle at the G2 phase. Thus, our modified approach can rapidly screen reliable, stable and high binding affinity aptamers for precise cancer treatment.


Assuntos
Aptâmeros de Nucleotídeos/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Animais , Aptâmeros de Nucleotídeos/química , Carbocianinas/química , Proliferação de Células/efeitos dos fármacos , DNA de Cadeia Simples/química , DNA de Cadeia Simples/metabolismo , Doxorrubicina/química , Doxorrubicina/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HEK293 , Células HL-60 , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Microscopia Confocal , Imagem Óptica , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Distribuição Tecidual , Transplante Heterólogo
10.
Gerontology ; 65(4): 323-331, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30541012

RESUMO

Alzheimer's disease (AD) affects nearly 50 million people worldwide, and currently no disease-modifying treatment is available. With continuous failure of anti-amyloid-beta- or tau-based therapies, identification of new targets has become an urgent necessity for AD prevention and therapy. Recently, conventional genetic approaches and computational strategies have converged on immune-inflammatory pathways as key events in the pathogenesis of AD. A number of genes have been highly linked to the onset and development of late-onset sporadic AD, the most common form of AD. Strikingly, most of these genes are involved in microglial biology. Mutations and/or differential expression of microglial receptors such as TREM2, CD33, and CR3 have been strongly associated with an increased risk of developing AD. The mechanistic actions of these risk factors in AD etiology have been actively investigated since they were identified. Whether these genes can be targeted for a disease-modifying treatment is under hot debate. CD33 is one of the top-ranked AD risk genes identified by genome-wide association studies. This review summarizes the recently advanced biology of CD33 and its association with AD. It also provides insights from a drug discovery perspective into the druggability, therapeutic strategies, and challenges to target CD33 for treating this devastating disorder.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Microglia/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Doença de Alzheimer/metabolismo , Descoberta de Drogas , Predisposição Genética para Doença , Humanos , Terapia de Alvo Molecular , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo
12.
J Immunother Cancer ; 6(1): 116, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30396365

RESUMO

Acute myeloid leukemia (AML) is the most common acute leukemia amongst adults with a 5-year overall survival lower than 30%. Emerging evidence suggest that immune alterations favor leukemogenesis and/or AML relapse thereby negatively impacting disease outcome. Over the last years myeloid derived suppressor cells (MDSCs) have been gaining momentum in the field of cancer research. MDSCs are a heterogeneous cell population morphologically resembling either monocytes or granulocytes and sharing some key features including myeloid origin, aberrant (immature) phenotype, and immunosuppressive activity. Increasing evidence suggests that accumulating MDSCs are involved in hampering anti-tumor immune responses and immune-based therapies. Here, we demonstrate increased frequencies of CD14+ monocytic MDSCs in newly diagnosed AML that co-express CD33 but lack HLA-DR (HLA-DRlo). AML-blasts induce HLA-DRlo cells from healthy donor-derived monocytes in vitro that suppress T-cells and express indoleamine-2,3-dioxygenase (IDO). We investigated whether a CD33/CD3-bispecific BiTE® antibody construct (AMG 330) with pre-clinical activity against AML-blasts by redirection of T-cells can eradicate CD33+ MDSCs. In fact, T-cells eliminate IDO+CD33+ MDSCs in the presence of AMG 330. Depletion of total CD14+ cells (including MDSCs) in peripheral blood mononuclear cells from AML patients did not enhance AMG 330-triggered T-cell activation and expansion, but boosted AML-blast lysis. This finding was corroborated in experiments showing that adding MDSCs into co-cultures of T- and AML-cells reduced AML-blast killing, while IDO inhibition promotes AMG 330-mediated clearance of AML-blasts. Taken together, our results suggest that AMG 330 may achieve anti-leukemic efficacy not only through T-cell-mediated cytotoxicity against AML-blasts but also against CD33+ MDSCs, suggesting that it is worth exploring the predictive role of MDSCs for responsiveness towards an AMG 330-based therapy.


Assuntos
Leucemia Mieloide Aguda/imunologia , Monócitos/metabolismo , Células Supressoras Mieloides/imunologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino
13.
Cell Death Dis ; 9(7): 763, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29988030

RESUMO

Myeloid-derived suppressor cells (MDSCs) are a prominent component of the pro-tumoral response. The phenotype of and mechanisms used by MDSCs is heterogeneous and requires more precise characterization in gastric cancer (GC) patients. Here, we have identified a novel subset of CD45+CD33lowCD11bdim MDSCs in the peripheral blood of GC patients compared to healthy individuals. CD45+CD33lowCD11bdim MDSCs morphologically resembled neutrophils and expressed high levels of the neutrophil marker CD66b. Circulating CD45+CD33lowCD11bdim MDSCs effectively suppressed CD8+ T cells activity through the inhibition of CD8+ T cell proliferation and interferon-γ (IFN-γ) and granzyme B (GrB) production. The proportion of CD45+CD33lowCD11bdim MDSCs also negatively correlated with the proportion of IFN-γ+CD8+ T cell in the peripheral blood of GC patients. GC patient serum-derived IL-6 and IL-8 activated and induced CD45+CD33lowCD11bdim MDSCs to express arginase I via the PI3K-AKT signaling pathway. This pathway contributed to CD8+ T cell suppression as it was partially rescued by the blockade of the IL-6/IL-8-arginase I axis. Peripheral blood CD45+CD33lowCD11bdim MDSCs, as well as IL-6, IL-8, and arginase I serum levels, positively correlated with GC progression and negatively correlated with overall patient survival. Altogether, our results highlight that a subset of neutrophilic CD45+CD33lowCD11bdim MDSCs is functionally immunosuppressive and activated via the IL-6/IL-8-arginase I axis in GC patients.


Assuntos
Arginase/metabolismo , Antígeno CD11b/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Células Supressoras Mieloides/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Arginase/genética , Western Blotting , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
14.
Future Oncol ; 14(30): 3199-3213, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30039981

RESUMO

In September 2017, the US FDA announced re-approval of gemtuzumab ozogamicin (GO), a CD33-targeting immunoconjugate, for treatment of newly diagnosed and relapsed/refractory acute myeloid leukemia (AML). This is a very significant step toward defining new treatment regimens in AML, as the treatment has essentially stayed unchanged with the '7 + 3 induction regimen' (7 days cytarabine and 3 days of anthracycline) since 1973. GO is the first antibody-drug conjugate to receive FDA approval for treating cancer. This review article discusses the challenges faced and lessons learned during the journey of GO for AML treatment. Selected trials that have made significant contribution in our understanding of the most efficacious and safe use of GO for treating AML patients as well as factors influencing GO response are highlighted in this article.


Assuntos
Aminoglicosídeos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Fatores Etários , Aminoglicosídeos/administração & dosagem , Aminoglicosídeos/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Descoberta de Drogas , França , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Terapia de Alvo Molecular , Ensaios Clínicos Controlados Aleatórios como Assunto , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Resultado do Tratamento , Estados Unidos
15.
Nat Cell Biol ; 20(6): 710-720, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29802403

RESUMO

Elucidation of the identity and diversity of mechanisms that sustain long-term human blood cell production remains an important challenge. Previous studies indicate that, in adult mice, this property is vested in cells identified uniquely by their ability to clonally regenerate detectable, albeit highly variable levels and types, of mature blood cells in serially transplanted recipients. From a multi-parameter analysis of the molecular features of very primitive human cord blood cells that display long-term cell outputs in vitro and in immunodeficient mice, we identified a prospectively separable CD33+CD34+CD38-CD45RA-CD90+CD49f+ phenotype with serially transplantable, but diverse, cell output profiles. Single-cell measurements of the mitogenic response, and the transcriptional, DNA methylation and 40-protein content of this and closely related phenotypes revealed subtle but consistent differences both within and between each subset. These results suggest that multiple regulatory mechanisms combine to maintain different cell output activities of human blood cell precursors with high regenerative potential.


Assuntos
Proliferação de Células , Separação Celular/métodos , Sangue Fetal/citologia , Mitose , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Análise de Célula Única/métodos , Células-Tronco/metabolismo , Animais , Biomarcadores/metabolismo , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Metilação de DNA , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Genótipo , Humanos , Masculino , Camundongos Transgênicos , Fenótipo , Fatores de Tempo , Transcriptoma
16.
Dev Comp Immunol ; 86: 219-231, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29751010

RESUMO

Siglecs (sialic acid-binding immunoglobulin-type lectins) are a family of immune regulatory receptors predominantly found on the cells of the hematopoietic system. A V-set Ig-like domain mediates the recognition of different sialylated glycoconjugates, which can lead to the activation or inhibition of the immune response, depending on the involved Siglecs. Siglecs are categorized into two subgroups: one including all CD33-related Siglecs and the other consisting of Siglec-1 (Sialoadhesin), Siglec-2 (CD22), Siglec-4 (myelin-associated glycoprotein, MAG) and Siglec-15. In contrast to the members of the CD33-related Siglecs, which share ∼50-99% sequence identity, Siglecs of the other subgroup show quite low homology (approximately 25-30% sequence identity). Based on the published sequences and functions of Siglecs, we performed phylogenetic analyses and sequence alignments to reveal the conservation of Siglecs throughout evolution. Therefore, we focused on the presence of Siglecs in different classes of vertebrates (fishes, amphibians, birds, reptiles and mammals), offering a bridge between the presence of different Siglecs and the biological situations of the selected animals.


Assuntos
Imunoglobulinas/genética , Lectinas/genética , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/genética , Ácidos Siálicos/metabolismo , Sequência de Aminoácidos , Animais , Evolução Molecular , Imunoglobulinas/metabolismo , Lectinas/metabolismo , Filogenia , Alinhamento de Sequência , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Vertebrados/genética , Vertebrados/metabolismo
17.
Oncologist ; 23(9): 1103-1108, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29650683

RESUMO

On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin (GO; Mylotarg; Pfizer, New York City, NY) for treatment of relapsed or refractory (R/R) CD33-positive acute myeloid leukemia (AML) in patients 2 years of age and older. GO is a CD33-directed antibody drug conjugate linked to the cytotoxic antibiotic calicheamicin. It originally received accelerated approval for treatment of older patients with relapsed CD33-positive AML in 2000, but it was withdrawn from the market in 2010 when the confirmatory trial failed to demonstrate clinical benefit among safety concerns, such as a higher rate of induction fatalities on the GO combination arm compared with chemotherapy alone. In addition, GO was associated with hepatic veno-occlusive disease (VOD), which has substantial morbidity and mortality. Pharmacokinetic analyses suggested a lower maximum concentration of GO would result in less VOD without affecting target saturation or efficacy. A meta-analysis across dose schedules of GO in patients with R/R AML showed that a lower-dose "fractionated" schedule of 3 mg/m2 days 1, 4, and 7 was associated with less early mortality, hemorrhage, and VOD, without an apparent decrease in complete remission (CR) rate. MyloFrance 1 was a single-arm study evaluating response rates in patients with relapsed CD33-positive AML treated with the lower-dose fractionated GO regimen. The CR rate was 26% (95% confidence interval 16%-40%). Common adverse reactions were fever, infections, nausea, vomiting, constipation, bleeding, increased liver enzymes, and mucositis. There were no cases of VOD. These results supported the approval of GO as monotherapy for R/R CD33-positive AML using the lower-dose fractionated regimen. IMPLICATIONS FOR PRACTICE: Gemtuzumab ozogamicin (GO) 3 mg/m2 days 1, 4, and 7 is an active regimen for induction of remission when used to treat patients with relapsed or refractory CD33-positive acute myeloid leukemia without curative intent. The risks of hepatic veno-occlusive disease and early mortality with this regimen appear to be lower than reported previously for GO 9 mg/m2 days 1 and 15. The data were not sufficient to enable conclusions about the safety of GO in children younger than 2 years of age.


Assuntos
Aminoglicosídeos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminoglicosídeos/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Humanos , Leucemia Mieloide Aguda/patologia , Pessoa de Meia-Idade , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Estados Unidos , United States Food and Drug Administration , Adulto Jovem
18.
Clin Cancer Res ; 24(14): 3242-3246, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29476018

RESUMO

On September 1, 2017, the FDA granted approval for gemtuzumab ozogamicin (Mylotarg; Pfizer Inc.) in combination with daunorubicin and cytarabine and as a monotherapy for the treatment of adult patients with newly diagnosed CD33-positive acute myeloid leukemia (AML). Gemtuzumab ozogamicin is a CD33-targeted antibody-drug conjugate joined to calicheamicin. Approval of gemtuzumab ozogamicin combination treatment was based on a randomized trial of 271 patients with newly diagnosed AML treated with daunorubicin and cytarabine with or without 3 mg/m2 fractionated gemtuzumab ozogamicin, which resulted in an event-free survival (EFS) of 13.6 months for gemtuzumab ozogamicin + daunorubicin and cytarabine and 8.8 months for daunorubicin and cytarabine alone [HR = 0.68 (95% confidence interval (CI), 0.51-0.91)]. Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with gemtuzumab ozogamicin + daunorubicin and cytarabine. Approval of gemtuzumab ozogamicin monotherapy was based on a randomized trial of 237 patients with newly diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with gemtuzumab ozogamicin versus 3.6 months on best supportive care [HR = 0.69 (95% CI, 0.53-0.90)]. Adverse events were similar on both arms. Postapproval, several studies are required including evaluation of fractionated gemtuzumab ozogamicin pharmacokinetics, safety of combination gemtuzumab ozogamicin in the pediatric population, immunogenicity, and the effects of gemtuzumab ozogamicin on platelet function. Clin Cancer Res; 24(14); 3242-6. ©2018 AACR.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Aprovação de Drogas , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Adulto , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Leucemia Mieloide Aguda/diagnóstico , Resultado do Tratamento
19.
Dev Comp Immunol ; 84: 117-122, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29427600

RESUMO

Siglec-3/CD33 is a myeloid-specific inhibitory receptor that is expressed on cells of the immune system, where it is believed to play a regulatory role, modulating the inflammatory and immune responses. We characterized CD33 (RbCD33) in rock bream which is a transmembrane protein with two IG-like domains and a cytoplasmic tail. It has a deduced amino acid sequence of 390 residues and has tyrosine-based signaling motifs in the cytoplasmic tail. The RbCD33 mRNA was highly expressed in peripheral blood leukocytes and was also detected in the muscle, spleen, skin, head kidney, gills, trunk kidney, heart, stomach, brain, intestine and liver by quantitative real-time PCR. A temporal variation in expression of RbCD33 was observed in different tissues after stimulating with E. tarda, S. iniae and red seabream iridovirus (RSIV). In the head kidney tissue, E. tarda and S. iniae induced RbCD33, while a down regulation was observed with RSIV. In addition, in spleen tissue, S. iniae caused a very high induction of RbCD33 in comparison with an E. tarda and RSIV challenge. In the liver and gill tissues, all three pathogens induced a high expression of RbCD33. The expression pattern in various tissues and its high induction after pathogen stimulation suggests that RbCD33 plays an important role in initiating the immune response via the inhibition of signal transduction of the myeloid lineage cells.


Assuntos
Infecções por Vírus de DNA/imunologia , Edwardsiella tarda/imunologia , Infecções por Enterobacteriaceae/imunologia , Doenças dos Peixes/imunologia , Proteínas de Peixes/genética , Brânquias/fisiologia , Rim Cefálico/fisiologia , Iridovirus/fisiologia , Leucócitos Mononucleares/fisiologia , Fígado/fisiologia , Células Mieloides/fisiologia , Perciformes/imunologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Infecções Estreptocócicas/imunologia , Streptococcus iniae/imunologia , Zoonoses/imunologia , Animais , Clonagem Molecular , Proteínas de Peixes/metabolismo , Regulação da Expressão Gênica/imunologia , Brânquias/microbiologia , Brânquias/virologia , Rim Cefálico/microbiologia , Rim Cefálico/virologia , Humanos , Imunidade Inata , Imunomodulação , Fígado/microbiologia , Fígado/virologia , Perciformes/microbiologia , Perciformes/virologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Transdução de Sinais
20.
Mol Immunol ; 94: 107-120, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29291452

RESUMO

Myeloid-derived suppressor cells (MDSCs) have recently been described to inhibit protective T-cell responses in tuberculosis (TB). T cells play an important role in the immunity to Mycobacterium tuberculosis, and are the major producers of IFN-γ. However, the impact of IFN-γ on MDSCs during TB is still not completely understood. Our study demonstrated a significant correlation between MDSC levels and TB progression, suggesting that MDSCs may serve as a potential marker in diagnosis or treatment of TB. Culture with GM-csf and IL-6 promoted peripheral blood mononuclear cells (PBMCs) to differentiate into functional CD33+HLA-DRlow MDSC-like cells. Moreover, we report for the first time, that IFN-γ-educated CD33+HLA-DRlow MDSCs have less suppressive potential to diminish T-cell responses, including IFN-γ production. Further investigations revealed that suppressive function of CD33+HLA-DRlow MDSCs was dependent on programmed death-1/programmed death-1 ligand-2 (PD1/PD-L2) pathway and required direct cell-cell contact. IFN-γ dampened the immuno-suppressive activity of CD33+HLA-DRlow MDSCs by inhibiting PD-1/PD-L2 pathway, indicating the existence of a negative-feedback loop between IFN-γ and functional MDSC expansion. In summary, our study revealed a novel mechanism by which IFN-γ decreases the suppressive function of MDSCs, suggesting that antagonizing suppressive functions of MDSCs by IFN-γ could enhance immune responses against TB infection.


Assuntos
Antígenos HLA-DR/metabolismo , Interferon gama/farmacologia , Células Mieloides/efeitos dos fármacos , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Adolescente , Adulto , Idoso , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células Mieloides/patologia , Células Mieloides/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Tuberculose Pulmonar/metabolismo , Tuberculose Pulmonar/patologia , Adulto Jovem
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