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1.
Immunology ; 159(1): 75-87, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31587253

RESUMO

Dendritic cell (DC) -based cancer immunotherapy is one of the most important anti-cancer immunotherapies, and has been associated with variable efficiencies in different cancer types. It is well-known that tumor microenvironment plays a key role in the efficacy of various immunotherapies such as DC vaccine. Accordingly, the expression of programmed death ligand 1 (PD-L1) on DCs, which interacts with PD-1 on T cells, leads to inhibition of anti-tumor responses following presentation of tumor antigens by DCs to T cells. Therefore, we hypothesized that down-regulation of PD-L1 in DCs in association with silencing of PD-1 on T cells may lead to the enhancement of T-cell priming by DCs to have efficient anti-tumor T-cell responses. In this study, we silenced the expression of PD-L1 in DCs and programmed cell death protein 1 (PD-1) in T cells by small interfering RNA (siRNA) -loaded chitosan-dextran sulfate nanoparticles (NPs) and evaluated the DC phenotypic and functional characteristics and T-cell functions following tumor antigen recognition on DCs, ex vivo. Our results showed that synthesized NPs had good physicochemical characteristics (size 77·5 nm and zeta potential of 14·3) that were associated with efficient cellular uptake and target gene silencing. Moreover, PD-L1 silencing was associated with stimulatory characteristics of DCs. On the other hand, presentation of tumor antigens by PD-L1-negative DCs to PD-1-silenced T cells led to induction of potent T-cell responses. Our findings imply that PD-L1-silenced DCs can be considered as a potent immunotherapeutic approach in combination with PD-1-siRNA loaded NPs, however; further in vivo investigation is required in animal models.


Assuntos
Antígeno B7-H1/imunologia , Neoplasias da Mama/terapia , Vacinas Anticâncer/imunologia , Neoplasias do Colo/terapia , Células Dendríticas/transplante , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/imunologia , Terapêutica com RNAi , Linfócitos T/imunologia , Animais , Apoptose , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Técnicas de Cocultura , Neoplasias do Colo/genética , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Linfócitos do Interstício Tumoral/metabolismo , Camundongos Endogâmicos BALB C , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais , Linfócitos T/metabolismo
2.
Nat Biotechnol ; 37(11): 1322-1331, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31570897

RESUMO

The near-infrared-IIb (NIR-IIb) (1,500-1,700 nm) window is ideal for deep-tissue optical imaging in mammals, but lacks bright and biocompatible probes. Here, we developed biocompatible cubic-phase (α-phase) erbium-based rare-earth nanoparticles (ErNPs) exhibiting bright downconversion luminescence at ~1,600 nm for dynamic imaging of cancer immunotherapy in mice. We used ErNPs functionalized with cross-linked hydrophilic polymer layers attached to anti-PD-L1 (programmed cell death-1 ligand-1) antibody for molecular imaging of PD-L1 in a mouse model of colon cancer and achieved tumor-to-normal tissue signal ratios of ~40. The long luminescence lifetime of ErNPs (~4.6 ms) enabled simultaneous imaging of ErNPs and lead sulfide quantum dots emitting in the same ~1,600 nm window. In vivo NIR-IIb molecular imaging of PD-L1 and CD8 revealed cytotoxic T lymphocytes in the tumor microenvironment in response to immunotherapy, and altered CD8 signals in tumor and spleen due to immune activation. The cross-linked functionalization layer facilitated 90% ErNP excretion within 2 weeks without detectable toxicity in mice.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Antígeno B7-H1/imunologia , Neoplasias do Colo/tratamento farmacológico , Érbio/química , Animais , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Antígenos CD8/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Imunoterapia , Raios Infravermelhos , Camundongos , Nanopartículas , Imagem Óptica , Pontos Quânticos , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Food Funct ; 10(9): 5816-5826, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31463494

RESUMO

Several studies have shown that mushroom polysaccharides enhance the ability of natural killer (NK) cells to recognize cancer cells as foreign and thereby enhance the effectiveness of host immune defence mechanisms. Nevertheless, the use of NK cells in cancer treatment requires finding selective stimulators of their cytotoxicity without disturbing organism homeostasis. Our studies revealed that Cantharellus cibarius polysaccharides present in the CC2a fraction, mainly composed of an O-2 and O-3 branched (1→6)-linked mannan, not only beneficially influenced the viability and proliferation of the human natural killer cells NK92 but also enhanced their anticancer properties against the human lung and colon cancer cells A549 and LS180, and at the same time did not affect the human lung and colon epithelial cells NL20 and CCD841 CoN. Furthermore, the CC2a fraction used alone was also nontoxic to the normal epithelium, while it inhibited the viability of these cancer cells. Nevertheless, the therapeutic potential of NK92 cells was greatly enhanced after coincubation with these polysaccharides and the observed effect was dependent on the CC2a concentrations. The beneficial effect of CC2a on NK92 cells was associated with stimulation of p38 and Erk expression as well as induction of the transcription factor CREB. The discovered beneficial impact of the CC2a fraction on NK92 cells suggested the therapeutic use of the investigated compound especially as an adjuvant. Furthermore, taking into account the abundance of these water soluble mannans in C. cibarius, the results also suggest that an increase in the intake of C. cibarius may promote innate immunity response against cancer through the enhancement of NK cell activity.


Assuntos
Agaricales/química , Antineoplásicos Fitogênicos/farmacologia , Neoplasias do Colo/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Neoplasias Pulmonares/imunologia , Mananas/farmacologia , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/química , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/fisiopatologia , Humanos , Imunidade Inata/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/fisiopatologia , Mananas/química , Extratos Vegetais/química
4.
Cancer Sci ; 110(10): 3027-3037, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31348591

RESUMO

We previously established a method to generate myeloid cells with a proliferative capability from pluripotent stem cells and designated them iPS-ML. Human iPS-ML cells share features with physiological macrophages including the capability to infiltrate into cancer tissues. We observed therapeutic effects of human iPS-ML cells expressing interferon ß (iPS-ML/interferon (IFN)-ß) in xenograft cancer models. However, assessment of host immune system-mediated therapeutic and adverse effects of this therapy is impossible by xenograft models. We currently evaluated the therapeutic effects of a mouse equivalent of human iPS-ML/IFN, a mouse embryonic stem (ES) cell-derived myeloid cell line producing IFN (ES-ML/IFN). The ES-MLs producing IFN-ß (ß-ML) and IFN-γ (γ-ML) and originating from E14 ES cells derived from the 129 mouse strain (H-2b ) were generated, and the MHC (H-2Kb , Db , and I-Ab ) genes of the ES-ML/IFN were disrupted using the clustered regularly interspaced short palindromic repeats (CRISPR)/CAS9 method. We used the ES-ML/IFN to treat allogeneic BALB/c mice (H-2d ) transplanted with Colon26 cancer cells. Treatment with ß-ML but not with γ-ML cells repressed the growth of colon cancer in the peritoneal cavity and liver. The transferred ES-ML/IFN infiltrated into cancer tissues and enhanced infiltration of T cells into cancer tissues. ES-ML/IFN therapy increased the number of immune cells in the lymphoid organs. Sensitization of both cancer antigen-specific CD8+ T cells and natural killer (NK) cells were enhanced by the therapy, and CD8+ T cells were essential for the therapeutic effect, implying that donor MHC-deficient ß-ML exhibited a therapeutic effect through the activation of host immune cells derived from allogeneic recipient mice. The results suggested the usefulness of HLA-deficient human iPS-ML/IFN-ß cells for therapy of HLA-mismatched allogeneic cancer patients.


Assuntos
Neoplasias do Colo/terapia , Células-Tronco Embrionárias/citologia , Antígenos de Histocompatibilidade/genética , Interferon beta/metabolismo , Células Mieloides/transplante , Animais , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Células-Tronco Embrionárias/metabolismo , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células Matadoras Naturais/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Células Mieloides/citologia , Células Mieloides/metabolismo , Transplante Homólogo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Glycoconj J ; 36(5): 399-408, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31267246

RESUMO

Even though a vaccine that targets tumor-associated carbohydrate antigens on epithelial carcinoma cells presents an attractive therapeutic approach, relatively poor immunogenicity limits its development. In this study, we investigated the immunological activity of a fluoro-substituted Sialyl-Tn (F-STn) analogue coupled to the non-toxic cross-reactive material of diphtheria toxin197 (CRM197). Our results indicate that F-STn-CRM197 promotes a greater immunogenicity than non-fluorinated STn-CRM197. In the presence or absence of adjuvant, F-STn-CRM197 remarkably enhances both cellular and humoral immunity against STn by increasing antigen-specific lymphocyte proliferation and inducing a mixed Th1/Th2 response leading to production of IFN-γ and IL-4 cytokines, as well as STn-specific antibodies. Furthermore, antisera produced from F-STn-CRM197 immunization significantly recognizes STn-positive tumor cells and increases cancer cell lysis induced by antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) pathways. Our data suggest that this F-STn vaccine may be useful for cancer immunotherapy and possibly for prophylactic prevention of cancer.


Assuntos
Anticorpos Antineoplásicos/farmacologia , Antígenos Glicosídicos Associados a Tumores/química , Proteínas de Bactérias/farmacologia , Vacinas Anticâncer/farmacologia , Neoplasias do Colo/terapia , Glicoconjugados/farmacologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Anticorpos Antineoplásicos/isolamento & purificação , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antígenos Glicosídicos Associados a Tumores/imunologia , Proteínas de Bactérias/química , Proteínas de Bactérias/imunologia , Vacinas Anticâncer/síntese química , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Feminino , Expressão Gênica , Glicoconjugados/síntese química , Glicoconjugados/imunologia , Halogenação , Humanos , Soros Imunes/química , Soros Imunes/farmacologia , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Imunização , Imunogenicidade da Vacina , Interferon gama/genética , Interferon gama/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Baço/efeitos dos fármacos , Baço/imunologia , Equilíbrio Th1-Th2
6.
Int J Cancer ; 145(11): 3101-3111, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31344262

RESUMO

Colorectal cancer is a highly metastatic disease that could invade various distal organs and also the peritoneal cavity leading to peritoneal carcinomatosis. This is a terminal condition with poor prognosis and only palliative treatments such as cytoreductive surgery and intraperitoneal chemotherapy are proposed to some patients. However, clinicians use different parameters of treatments without any consensus. Here we decided to evaluate the effect of osmolarity in the efficacy of this procedure to kill colon cancer cells. We first show that a short exposure of platinum derivatives in hypotonic conditions is more efficient to decrease cell viability of human and murine colon cancer cells in vitro as compared to isotonic conditions. This is related to more important incorporation of platinum and the capacity of hypotonic stress to induce the copper transporter CTR1 oligomerization. Oxaliplatin in hypotonic conditions induces caspase-dependent cell death of colon cancer cells. Moreover, hypotonic conditions also modulate the capacity of oxaliplatin and cisplatin (but not carboplatin) to induce immunogenic cell death (ICD). In vivo, oxaliplatin in hypotonic conditions increases CD8+ T cell tumor infiltration and activation. Finally, in a murine peritoneal carcinomatosis model, oxaliplatin in hypotonic conditions is the only tested protocol which is able to slow down the appearance of tumor nodules and increase mice survival, while showing no effect in CD8+ T cells depleted mice or in immunodeficient mice. Altogether, our study provides new information both in vitro and in a preclinical model of peritoneal carcinomatosis, which highlights the importance of hypoosmolarity in intraperitoneal chemotherapy.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Neoplasias do Colo/tratamento farmacológico , Pressão Osmótica , Oxaliplatina/administração & dosagem , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/secundário , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/imunologia , Feminino , Células HCT116 , Células HT29 , Humanos , Injeções Intraperitoneais , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Oxaliplatina/farmacologia , Neoplasias Peritoneais/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Life Sci Alliance ; 2(4)2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31249132

RESUMO

NADPH oxidases catalyze the production of reactive oxygen species and are involved in physio/pathological processes. NOX1 is highly expressed in colon cancer and promotes tumor growth. To investigate the efficacy of NOX1 inhibition as an anticancer strategy, tumors were grown in immunocompetent, immunodeficient, or NOX1-deficient mice and treated with the novel NOX1-selective inhibitor GKT771. GKT771 reduced tumor growth, lymph/angiogenesis, recruited proinflammatory macrophages, and natural killer T lymphocytes to the tumor microenvironment. GKT771 treatment was ineffective in immunodeficient mice bearing tumors regardless of their NOX-expressing status. Genetic ablation of host NOX1 also suppressed tumor growth. Combined treatment with the checkpoint inhibitor anti-PD1 antibody had a greater inhibitory effect on colon carcinoma growth than each compound alone. In conclusion, GKT771 suppressed tumor growth by inhibiting angiogenesis and enhancing the recruitment of immune cells. The antitumor activity of GKT771 requires an intact immune system and enhances anti-PD1 antibody activity. Based on these results, we propose blocking of NOX1 by GKT771 as a potential novel therapeutic strategy to treat colorectal cancer, particularly in combination with checkpoint inhibition.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , NADPH Oxidase 1/antagonistas & inibidores , NADPH Oxidases/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Imunoterapia , Interferon gama/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/farmacologia , Microambiente Tumoral/imunologia
8.
Monoclon Antib Immunodiagn Immunother ; 38(4): 157-161, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31199696

RESUMO

The expression of human epidermal growth factor receptor 2 (HER2) has been reported to be overexpressed in several cancers, such as breast, lung, gastric, pancreatic, and colorectal cancers, and be associated with poor clinical outcomes. Trastuzumab, a humanized anti-HER2 antibody, provides significant survival benefits for patients with HER2-overexpressing breast cancers and gastric cancers. In this study, we developed a novel anti-HER2 monoclonal antibody (mAb), H2Mab-41 (IgG2b, kappa), and the antitumor activity of H2Mab-41 was investigated using mouse xenograft models. Caco-2 cells (human colon cancer cell line), which expresses HER2, were subcutaneously implanted into the flanks of nude mice. H2Mab-41 and control mouse IgG were injected three times into the peritoneal cavity of mice. H2Mab-41 significantly reduced tumor development of Caco-2 xenograft in comparison with the control mouse IgG on days 5, 8, 11, 15, and 19. Taken together, these results suggest that H2Mab-41 is useful for antibody therapy against HER2-expressing colon cancers.


Assuntos
Anticorpos Monoclonais/farmacologia , Neoplasias do Colo/prevenção & controle , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/imunologia , Animais , Anticorpos Monoclonais/imunologia , Apoptose , Proliferação de Células , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(4): 307-312, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31167689

RESUMO

Objective To explore the effect of pexidartinib on the recruitment of monocytes into the tumor microenvironment and the polarization of M2 macrophages. Methods The colon cancer mouse model was established with the subcutaneous rejection of MC38 cells. After the tumor-bearing mice were treated with pexidartinib, we observed the effects of pexidartinib on the tumor growth, the survival of tumor-bearing mouse and the number of intratumoral tumor-associated macrophages (TAMs). Peripheral blood mononuclear cells were isolated from the enhanced green fluorescent protein (EGFPTg/+) transgenic mice and then transferred into the tumor-bearing mice via tail vein. After the tumor-bearing mice were treated with pexidartinib, the monocyte recruitment and the proportions of F4/80 and CD206-positive cells were detected by the immunofluorescence and flow cytometry. Results Pexidartinib alleviated the growth of MC38 cells in vivo and improved the survival rate in tumor-bearing mice. Pexidartinib reduced the number of TAMs and the formation of M2 TAMs in the tumor microenvironment, and inhibited the recruitment of monocytes from peripheral blood to the tumor microenvironment. Conclusion Pexidartinib can inhibit the tumor growth by suppressing the aggregation of macrophages and the number of M2 TAMs in the tumor microenvironment.


Assuntos
Aminopiridinas/farmacologia , Neoplasias do Colo/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Pirróis/farmacologia , Microambiente Tumoral , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Citometria de Fluxo , Leucócitos Mononucleares , Camundongos
10.
Biosci Trends ; 13(3): 216-224, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31168022

RESUMO

Protein glycosylation is a diverse form of post-translational modification. Two to three consecutive O-linked N-acetylgalactosamines (Tn-antigens) are recognized by antibodies such as MLS128. MLS128 mAb inhibited cell growth and bound to a 110 kDa glycoprotein (GP) in LS180 and HT29 colon cancer cells. However, purification and identification of the 110 kDa GP was unsuccessful due to its low abundance. The present study used a highly sophisticated and sensitive mass spectrometry method to identify proteins immunoprecipitated with MLS128 and separated by two-dimensional gel electrophoresis. Three desmosome components were identified. Of these, desmocollin and desmoglein shared many similar characteristics, including molecular mass, pI, and potential Tn-antigen sites. Western blotting analyses of LS180 cell lysates revealed a common 110 kDa band recognized by MLS128 and anti-desmocollin, but not by anti-desmoglein. Immunofluorescence microscopy of LS180 cells revealed that desmocollin is membrane-bound, while desmoglein is primarily localized in the cytosol. Confocal microscopy demonstrated colocalization of the desmocollin-specific antibody with the MLS128 antibody on the cell membrane, suggesting that desmocollin may contain Tn-antigens recognized by MLS128. Treatment of LS180 cells with siRNA to knock down desmocollin expression or a desmocollin-specific antibody decreased cell viability, suggesting a critical role for this protein in cell growth and survival. N-glycosidase F digestion of the 110 kDa GP and desmocollin suggested that although both proteins contain N-glycosylation sites, they are not identical. These findings suggest that desmocollin colocalizes with the 110 kDa GP and that growth inhibition induced by the MLS128 antibody may be mediated through a mechanism that involves desmocollin.


Assuntos
Neoplasias do Colo/metabolismo , Desmocolinas/metabolismo , Glicoproteínas/metabolismo , Anticorpos Monoclonais/imunologia , Antígenos Glicosídicos Associados a Tumores/imunologia , Antígenos Glicosídicos Associados a Tumores/metabolismo , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/imunologia , Desmocolinas/imunologia , Glicoproteínas/imunologia , Células HT29 , Humanos , Microscopia Confocal , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/metabolismo , Espectrometria de Massas em Tandem
11.
Ann Diagn Pathol ; 41: 69-78, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31146180

RESUMO

AIM: Tumour-infiltrating T lymphocytes (TIL) are considered to be a reliable prognostic marker in CC, but the use in daily practice is unclear. We investigated the survival effect of TIL methodologically in a highly homogeneous population. METHODS: Seventy-two stage IIA (T3N0) CC patients who underwent surgical resection from 2000 to 2014 were included. CD3 and CD8 were separately scored for different blocks, areas and foci. To the best of our knowledge, this study has the most comprehensive methodology in the literature. RESULTS: Foremost, we searched for the optimal evaluation method. We found better results with Model A (deepest invasive block&hot spot area&invasive margin focus), e.g. for CD3, the relationship with prognostic factors [Crohn's-like reaction (p = 0.015), positive surgical margin (p = 0.019), Mismatch repair proteins deficiency (p = 0.003), advanced grade (p = 0.015)], the correlation of distinct estimates (r = 0.708), the reproducibility of research (Κappa = 0.60-0.71), and the usefulness of cut-off value (area of under ROC = 0.800 [0.683-0.917]) were best. Then, survival analysis was performed with two better methods including Model A. In univariate analysis, low TIL with Model A was associated with worse OS (CD3, p < 0.001; CD8, p = 0.023) and RFS (CD3, p < 0.001; CD8, p = 0.005). Multivariate analyses confirmed low TIL with same method as an independent worse prognostic marker for OS (CD3, Hazard ratio [HR] = 1.42 [1.10-1.85], p = 0.005) and RFS (CD3, HR = 1.46 [1.17-1.83], p = 0.001; CD8, HR = 1.32 [1.05-1.64], p = 0.032). CONCLUSIONS: Our results confirm that low TIL is an independent worse prognostic marker in stage IIA (T3N0) CC and that the use of CD3 with Model A can contribute to improving the prognostication of early CCs.


Assuntos
Neoplasias do Colo/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/imunologia , Neoplasias do Colo/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
12.
Oncol Rep ; 42(1): 386-398, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31059103

RESUMO

Cancer stem cells (CSCs) serve an important role in tumorigenesis, tolerance to treatment, relapse and metastasis. Although the signaling pathways involved in cancer are well known, the molecular mechanisms underlying CSC actions require further investigation. In the present study, a population of colon CSCs with a cluster of differentiation 133 (CD133) surface­expression phenotype from the human SW480 colon adenocarcinoma cell line were isolated by flow cytometry. The CD133+ cells exhibited increased tumor sphere­forming efficiency in vitro and increased tumorigenic potential in vivo. Furthermore, the gene expression profile of colon CSCs was investigated using gene chip technology. The results demonstrated differential gene expression between the CD133+ and CD133­ subpopulations, including in relation to a number of important genes with functions in transcription control, cell cycle, karyomitosis and protein phosphorylation, including cyclin dependent kinase inhibitor 1A, cyclin B1, checkpoint kinase 1, cyclin dependent kinase 1 and transforming growth factor ß receptor 2. Pathway analysis revealed that the mitogen­activated protein kinase, p53 and calcium signaling pathways, as well as other important signaling pathways, were differentially activated between CD133+ and CD133­ cells. To the best of our knowledge, these results provide the first evidence for the gene expression profile of colon CSCs in the SW480 colon adenocarcinoma cell line. Although further studies will be required to identify the functional roles of these genes in the CSC phenotype, these observations provide the basis for future studies to elucidate the pathogenesis of colorectal cancer and to develop novel tumor­targeting therapies.


Assuntos
Antígeno AC133/metabolismo , Adenocarcinoma/genética , Neoplasias do Colo/genética , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Células-Tronco Neoplásicas/imunologia , Adenocarcinoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HT29 , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Transplante de Neoplasias , Células-Tronco Neoplásicas/química , Análise de Sequência com Séries de Oligonucleotídeos
13.
Chirurgia (Bucur) ; 114(2): 152-161, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31060646

RESUMO

In the fine balance between tumor invasion and our defensive systems, the role played by the adaptive immune response at the tumor site is critical. Beyond the fact that all the immune components of the innate and adaptive response can be observed to varying degrees in the tumor microenvironment, it appears that a high density of T cytotoxic and memory lymphocytes, in a context of Th1 immune orientation in the tumor and its invasion front, provides a prognostic marker of paramount importance for colorectal cancer and more generally all solid tumors. The understanding of the role of immunity in cancer, tailored during one century of intensive research, has led to a complete paradigm shift.based on a sharp dissection In order to show the major impact of this conceptual revolution, we herein retrace through the example of colorectal cancer, how an effective immune test, namely the "Immunoscore", has been developed. We also provide up to date data demonstrating the capacity of the Immunoscore to prognosticate with a better accuracy than the TME classification clinical outcomes and to guide therapeutic strategies.


Assuntos
Neoplasias do Colo/imunologia , Indicadores Básicos de Saúde , Neoplasias Retais/imunologia , Microambiente Tumoral/imunologia , Imunidade Adaptativa/imunologia , Humanos , Prognóstico , Células Th1/imunologia , Resultado do Tratamento
14.
Nature ; 569(7756): 428-432, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043740

RESUMO

Combined PD-1 and CTLA-4-targeted immunotherapy with nivolumab and ipilimumab is effective against melanoma, renal cell carcinoma and non-small-cell lung cancer1-3. However, this comes at the cost of frequent, serious immune-related adverse events, necessitating a reduction in the recommended dose of ipilimumab that is given to patients4. In mice, co-treatment with surrogate anti-PD-1 and anti-CTLA-4 monoclonal antibodies is effective in transplantable cancer models, but also exacerbates autoimmune colitis. Here we show that treating mice with clinically available TNF inhibitors concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, improves anti-tumour efficacy. Notably, TNF is upregulated in the intestine of patients suffering from colitis after dual ipilimumab and nivolumab treatment. We created a model in which Rag2-/-Il2rg-/- mice were adoptively transferred with human peripheral blood mononuclear cells, causing graft-versus-host disease that was further exacerbated by ipilimumab and nivolumab treatment. When human colon cancer cells were xenografted into these mice, prophylactic blockade of human TNF improved colitis and hepatitis in xenografted mice, and moreover, immunotherapeutic control of xenografted tumours was retained. Our results provide clinically feasible strategies to dissociate efficacy and toxicity in the use of combined immune checkpoint blockade for cancer immunotherapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Imunoterapia/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , /uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/imunologia , Colite/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/imunologia , Sulfato de Dextrana/farmacologia , Feminino , Doença Enxerto-Hospedeiro , Hepatite/tratamento farmacológico , Humanos , Ipilimumab/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Exp Clin Cancer Res ; 38(1): 190, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072360

RESUMO

BACKGROUND: One of the most potent costimulatory molecules involved in the recognition and killing of tumor cells is CD80. However, its role and the molecular mechanisms regulating its expression in sporadic colorectal carcinogenesis remain elusive. Here, we provide evidence for CD80 overexpression in human colon epithelial cells derived from preneoplastic mucosa. METHODS: Expression of CD80 on colonic epithelial cells isolated from normal human colonic mucosa, preneoplastic and neoplastic specimens was assessed by flow cytometry. WT and CD80KO mice received azoxymethane to induce colon preneoplastic lesions and sacrificed to perform histology, flow cytometry analysis and immunohistochemistry of colonic mucosa. Some WT mice were treated with a monoclonal anti-CD80 antibody following AOM administration. Primary colon epithelial cells and CT26 cell line were used to quantify the expression of CD80 in response to pro-oxidant stimuli. Specific pharmacological inhibitors and siRNA silencing were used to inhibit MAPK pathways and STAT3. RESULTS: CD80 expression was significantly increased in colon epithelial cells of human preneoplastic lesions. In the AOM model, CD80 impairment by administration of neutralizing antibodies or use of CD80 knockout mice enhanced dysplasia development. In vitro, CD80 upregulation was induced by oxidative stress in colon cancer cells and primary colon epithelial cells. In addition, reactive oxygen species could induce CD80 expression via the JNK and p38 MAPK pathways, that activated STAT3 transcription factor in colon cancer epithelial cells. CONCLUSION: This study provide evidence for a major role of CD80 in orchestrating immune surveillance of colon preneoplastic lesions and might help to develop novel approaches that exploit anti-tumor immunity to prevent and control colon cancer.


Assuntos
Antígeno B7-1/genética , Neoplasias do Colo/genética , Lesões Pré-Cancerosas/genética , Fator de Transcrição STAT3/genética , Animais , Antígeno B7-1/imunologia , Carcinogênese/genética , Carcinogênese/imunologia , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Imunofenotipagem/métodos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Knockout , Estresse Oxidativo/genética , Lesões Pré-Cancerosas/imunologia , Lesões Pré-Cancerosas/patologia , Cultura Primária de Células , Transdução de Sinais/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
16.
Monoclon Antib Immunodiagn Immunother ; 38(2): 75-78, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30969150

RESUMO

Cancer stem cells contribute to tumorigenesis, metastasis, recurrence, and chemoresistance. CD133/prominin-1-a pentaspan membrane glycoprotein-has been used as a stem cell biomarker for the isolation of stem-like cells from a variety of normal and pathological tissues. In our previous studies, we developed several anti-CD133 monoclonal antibodies using Cell-Based Immunization and Screening (CBIS) methods, followed by characterization of their efficacy by flow cytometry, western blotting, and immunohistochemical analyses. One of the 100 clones, CMab-43 (IgG2a, kappa), demonstrated a sensitive and specific reaction against colon cancer cells. This study aimed to investigate the antitumor activity of CMab-43. Caco-2 cells (human colon cancer cell line) were subcutaneously implanted into the flanks of nude mice. CMab-43 and control mouse IgG were injected three times into the peritoneal cavity of mice. Tumor formation was observed in the control and CMab-43-treated mice of Caco-2 xenograft models. CMab-43 significantly reduced tumor development of Caco-2 xenograft in comparison with the control mouse IgG on days 12, 14, and 17. Our results cumulatively suggest that CMab-43 is useful for antibody therapy against CD133-expressing colon cancers.


Assuntos
Antígeno AC133/imunologia , Anticorpos Monoclonais/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/imunologia , Animais , Anticorpos Monoclonais/imunologia , Neoplasias do Colo/patologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Immunol Res ; 2019: 2368249, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30931335

RESUMO

Tumour-associated macrophage (TAM) serves as the site in which most inflammatory cells coreside. It plays an important role in determining the progression and metastasis of a tumour. The characteristic of TAM is largely dependent on the stimuli present in its tumour microenvironment (TME). Under this environment, however, M2 macrophages are found to be in abundance compared to M1 macrophages which later promote tumour progression. Numerous studies have elucidated the relationship between TAM and the progression of tumour; hence, TAM has now been the subject of interest among researchers for anticancer therapy. This review discusses the role of TAM in colorectal cancer (CRC) and some of the potential candidates that could reeducate TAM to fight against CRC. It is with hope that this review will serve as the foundation in understanding TAM in CRC and helping other researchers to select the most suitable candidate to reeducate TAM that could assist in enhancing the tumouricidal activity of M1 macrophage and eventually repress the development of CRC.


Assuntos
Neoplasias do Colo/imunologia , Neoplasias do Colo/terapia , Macrófagos/imunologia , Microambiente Tumoral/imunologia , Progressão da Doença , Humanos , Macrófagos/classificação , Fenótipo
18.
Int J Mol Med ; 43(6): 2291-2302, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31017261

RESUMO

The main aim of the present study was to investigate the dual roles and mechanism of interleukin (IL)­18 in dextran sulfate sodium (DSS)­induced colitis. Firstly, meta­analysis was used to explore whether the levels of IL­18 were different in patients with colon cancer or inflammatory bowel disease. The results demonstrated that IL­18 (rs187238, ­137G/C) increased the incidence rate of colon cancer in patients, while IL­18 (rs187238, ­137G/C) decreased the incidence rate of ulcerative colitis or Crohn's disease in patients. Therefore, IL­18 (rs187238, ­137G/C) may have a dual function in colitis. Next, the functional role of IL­18 in colitis was further investigated, by use of a DSS­induced colitis mouse model. Pre­treatment of the mice with IL­18 increased body weight, augmented colon length, reduced inflammatory infiltration, promoted mucin (Muc)­2 expression, increased the function and quantity of goblet cells and increased the mRNA levels of resistin­like molecule (RELM) ß and trefoil factor family (TFF) 3 in mice with DSS­induced colitis, through the IL­22/STAT3 pathway. By contrast, treatment with IL­18 at later stages of the disease reduced body weight, decreased colon length, enhanced inflammatory infiltration and reduced Muc­2 expression, decreased the function and quantity of goblet cells and inhibited the mRNA levels of RELMß and TFF3 in mice with DSS­induced colitis. In conclusion, IL­18 served a dual function in colitis by regulating the function of goblet cells. The anti­inflammatory effects of IL­18 were observed in the early stage of colitis­induced inflammation, while the pro­inflammatory effects were observed in the later stages of the disease.


Assuntos
Colite/imunologia , Neoplasias do Colo/imunologia , Doença de Crohn/imunologia , Células Caliciformes/imunologia , Interleucina-18/imunologia , Animais , Colite/genética , Colite/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Doença de Crohn/genética , Doença de Crohn/patologia , Células Caliciformes/patologia , Humanos , Interleucina-18/genética , Interleucinas/imunologia , Masculino , Camundongos Endogâmicos C57BL , Taxa de Mutação , Polimorfismo de Nucleotídeo Único
19.
J Immunol ; 202(11): 3326-3333, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31019062

RESUMO

Inflammatory bowel diseases are known to be the origin of colitis-associated colon cancer (CAC). We previously reported that dextran sulfate sodium (DSS)-induced colitis is exacerbated in mouse-IL-21-isoform transgenic (Tg) mice. In this study, we assessed the CAC development induced by azoxymethane (AOM) and DSS in our Tg mice. AOM-DSS-induced tumor development was dramatically increased in the Tg mice compared with wild-type mice. IL-21 is known to enhance activation-induced cytidine deaminase (AID) expression in B cells and induce Ab class switching. In contrast, the AID expression in cells other than B cells initiates tumor development in many tissues. Therefore, we investigated whether IL-21 induces the AID expression in the large intestinal epithelial cells (IECs) during CAC development. AID gene and protein expression was increased in the IECs of AOM-DSS- or DSS-treated Tg mice compared with those of wild-type mice. Furthermore, we confirmed IL-21 induced AID gene expression in the purified IECs ex vivo. The present study also showed IL-21R gene expression in unstimulated wild-type mouse IECs, and this gene expression was augmented by TNF-α stimulation. The IL-21R expression and IL-21-induced AID gene activation were further confirmed in the Colon-38 cell line. Taken together, IL-21 may be involved in increasing the risk of CAC by enhancing the AID expression in IECs.


Assuntos
Linfócitos B/imunologia , Colite/imunologia , Neoplasias do Colo/imunologia , Doenças Inflamatórias Intestinais/imunologia , Interleucinas/metabolismo , Mucosa Intestinal/fisiologia , Animais , Azoximetano , Linhagem Celular Tumoral , Colite/induzido quimicamente , Neoplasias do Colo/induzido quimicamente , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Humanos , Switching de Imunoglobulina , Doenças Inflamatórias Intestinais/induzido quimicamente , Interleucinas/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos
20.
Clin J Gastroenterol ; 12(4): 330-335, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30903514

RESUMO

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer is a B-cell lymphoproliferative disorder occurring in elderly or iatrogenic immunocompromised patients. We report a 27-year-old male patient with Crohn's disease (CD) who developed immunomodulator-associated lymphoproliferative disorder. The patient was diagnosed with CD at the age of 17 and was treated with maintenance therapy including high-dose infliximab and azathioprine. When he was admitted to our hospital with a diagnosis of intestinal obstruction, his abdominal computed tomography findings showed not only colonic wall thickening and narrowing of the descending colon but also multiple liver tumor lesions. His ileus symptom improved with conservative therapy, and a pathological evaluation of the tissue biopsy specimens from the descending colon and liver lesions indicated a morphological diagnosis of EBV-positive diffuse large B-cell lymphoma. This was a case of iatrogenic immunodeficiency-associated lymphoproliferative disorder due to an immunomodulator. The treatment was initiated with chemotherapy, but he died of disease progression 10 months after the diagnosis of lymphoma. Although cases of lymphoproliferative disorder due to treatment modalities used for CD are rare in Japan, an increase in the risk of lymphoproliferative diseases should be considered in patients with CD treated with immunomodulatory agents.


Assuntos
Doença de Crohn/tratamento farmacológico , Infecções por Vírus Epstein-Barr/complicações , Imunossupressores/efeitos adversos , Linfoma Difuso de Grandes Células B/virologia , Adulto , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/imunologia , Neoplasias do Colo/virologia , Colonoscopia , Doença de Crohn/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Evolução Fatal , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/uso terapêutico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/virologia , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Tomografia Computadorizada por Raios X , Úlcera/imunologia , Úlcera/virologia
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