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1.
Anticancer Res ; 39(9): 4933-4940, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519598

RESUMO

BACKGROUND: Interleukin 2 (IL2) is a significant factor activating T-cell-mediated immune response by stimulation of natural killer cells, T-cells and in development of regulatory T (Treg) cells. Recent studies have that IL2 participates in cancer development by modifying the local immune response. Based on the suggested role of the single nucleotide polymorphisms (SNPs) rs2069762, rs6822844 and rs11938795 of IL2 in the pathogenesis of certain diseases, the relationship of these SNPs with clinicopathological variables and their possible implication for prognosis and disease outcome were evaluated in a cohort of Swedish patients with colorectal cancer (CRC). MATERIALS AND METHODS: TaqMan SNP genotype assays based on polymerase chain reaction were used for analysis of the IL2 SNPs in 467 patients with CRC and 467 healthy controls. Expression analysis of IL2 in plasma and CRC tissue was also performed. RESULTS: The allelic variants T in rs11938795 and G in rs6822844 were significantly associated with a higher risk of CRC. Kaplan-Meier analysis showed that cancer-specific survival was worse for individuals with C allele for rs2069762 with stage II CRC and with T allele for rs6822844 with stage III CRC. CONCLUSION: SNPs rs2069762, rs6822844 and rs11938795 of the IL2 gene may be helpful as prognostic biomarkers in the follow-up and management of the patients.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Variação Genética , Interleucina-2/genética , Adulto , Idoso , Alelos , Biomarcadores Tumorais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/imunologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Imunomodulação , Interleucina-2/sangue , Interleucina-2/metabolismo , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Prognóstico , Medição de Risco
2.
Cancer Sci ; 110(10): 3049-3060, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31390678

RESUMO

Heat shock protein 105 (HSP105) is overexpressed in many cancers, including colorectal cancer (CRC) and esophageal cancer (EC). We carried out a phase I clinical trial of HLA-A24- and HLA-A2-restricted HSP105 peptide vaccines in patients with CRC or EC. In this additional study of the trial, we examined the immunological efficacy of the novel vaccine. Thirty patients with advanced CRC or EC underwent HSP105 peptide vaccination. Immunological responses were evaluated by ex vivo and in vitro γ-interferon enzyme-linked immunospot assays and their correlation with patients' prognosis was analyzed. The HSP105 peptide vaccines induced peptide-specific CTLs in 15 of 30 patients. Among HLA-A24 patients (n = 15), 7 showed induction of CTLs only ex vivo, whereas among HLA-A2 patients (n = 15), 4 showed the induction ex vivo and 6 in vitro. Heat shock protein 105-specific CTL induction correlated with suppression of cancer progression and was revealed as a potential predictive biomarker for progression-free survival (P = .008; hazard ratio = 3.03; 95% confidence interval, 1.34-6.85) and overall survival (P = .025; hazard ratio = 2.72; 95% confidence interval, 1.13-6.52). Production of cytokines by HSP105 peptide-specific CTLs was observed at the injection sites (skin) and tumor tissues, suggesting that HSP105-specific CTLs not only accumulated at vaccination sites but also infiltrated tumors. Furthermore, we established 2 HSP105 peptide-specific CTL clones, which showed HSP105-specific cytokine secretion and cytotoxicity. Our results suggest that the HSP105 peptide vaccine could induce immunological effects in cancer patients and improve their prognosis.


Assuntos
Vacinas Anticâncer/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Proteínas de Choque Térmico HSP110/química , Proteínas de Choque Térmico HSP110/metabolismo , Adulto , Idoso , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Neoplasias Colorretais/imunologia , Citocinas/metabolismo , Intervalo Livre de Doença , Neoplasias Esofágicas/imunologia , Feminino , Antígeno HLA-A2/metabolismo , Antígeno HLA-A24/metabolismo , Células Hep G2 , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Linfócitos T Citotóxicos/imunologia , Resultado do Tratamento , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia
3.
Anticancer Res ; 39(8): 4525-4532, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366555

RESUMO

BACKGROUND/AIM: In this retrospective study, we aimed to investigate the efficacy of immune-cell therapy using T lymphocytes activated in vitro with or without dendritic cells vaccination (DCs), in combination with 1st-line chemotherapies in terms of the survival of patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS: A total of 198 patients who were diagnosed with advanced CRC and administered 1st-line chemotherapies were enrolled in this study. The correlation between overall survival (OS) and various clinical factors was examined by univariate and multivariate analyses. RESULTS: Univariate analyses revealed that the prognosis was improved in CRC patients who received immune-cell therapy with PS 0, bevacizumab (BV), and capecitabine-including regimens (Cap). Finally, multivariate analysis demonstrated that PS=0, and the combination of immune-cell therapy and Cap provided a survival benefit in patients with advanced CRC. CONCLUSION: The survival benefit could be potentially obtained with better PS by the combination of immune-cell therapy and Cap as a 1st-line setting in patients with CRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Imunoterapia , Prognóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/administração & dosagem , Capecitabina/administração & dosagem , Terapia Baseada em Transplante de Células e Tecidos , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Terapia Combinada , Desoxicitidina/administração & dosagem , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade
4.
Cancer Immunol Immunother ; 68(8): 1235-1243, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31214732

RESUMO

Off-target toxicity due to the expression of target antigens in normal tissue or TCR cross-reactivity represents a major risk when using T cell receptor (TCR)-engineered T cells for treatment of solid tumours. Due to the inherent cross-reactivity of TCRs it is difficult to accurately predict their target recognition pre-clinically. It has become evident that direct testing in a human being represents the best evaluation of the risks. There is, therefore, a clear unmet need for assessing the safety of a therapeutic TCR in a more controllable manner than by the injection of permanently modified cellular products. Using transiently modified T cells combined with dose escalation has already been shown feasible for chimeric antigen receptor (CAR)-engineered T cells, but nothing is yet reported for TCR. We performed a preclinical evaluation of a therapeutic TCR transiently expressed in T cells by mRNA electroporation. We analyzed if the construct was active in vitro, how long it was detectable for and if this expression format was adapted to in vivo efficacy assessment. Our data demonstrate the potential of mRNA engineered T cells, although less powerful than permanent redirection, to induce a significant response. Thus, these findings support the development of mRNA based TCR-therapy strategies as a feasible and efficacious method for evaluating TCR safety and efficacy in first-in-man testing.


Assuntos
Vacinas Anticâncer/imunologia , Neoplasias Colorretais/terapia , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Animais , Neoplasias Colorretais/imunologia , Reações Cruzadas , Citotoxicidade Imunológica , Eletroporação , Células HCT116 , Humanos , Camundongos , Camundongos SCID , Neoplasias Experimentais , RNA Mensageiro/genética , Receptores de Antígenos Quiméricos/genética , Especificidade do Receptor de Antígeno de Linfócitos T , Linfócitos T/transplante , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Zhonghua Nei Ke Za Zhi ; 58(6): 453-455, 2019 Jun 01.
Artigo em Chinês | MEDLINE | ID: mdl-31159526

RESUMO

The distribution of peripheral blood lymphocyte subsets were compared between patients with colorectal cancer and healthy controls. The number of natural killer(NK) cells and CD(8)(+)T cells and the percentage of naive CD(4)(+) T cells were all decreased significantly in patients. On the contrary, the percentages of memory CD(4)(+) T cells, HLA-DR(+) CD(8)(+) T cells and CD(38)(+) CD(8)(+) T cells were significantly increased. It suggests that the tumor killing effect of cytotoxic lymphocytes in peripheral blood is impaired in patients with colorectal cancer, whereas the immune response is over stimulated.


Assuntos
Neoplasias Colorretais/imunologia , Subpopulações de Linfócitos , Subpopulações de Linfócitos T , Neoplasias Colorretais/cirurgia , Humanos , Células Matadoras Naturais/imunologia , Contagem de Linfócitos
6.
Acta Histochem ; 121(5): 657-663, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31153587

RESUMO

The prognostic significance and clinical implications of resident CD103+CD8+T cells in human colorectal cancer tissues still remains largely unexplored. In our present study, we aimed to characterize the resident CD8+T cells in human colorectal cancer tissues by using double staining of CD103 and CD8, and further evaluated the prognostic significance of resident CD8+T cells in colorectal cancer. We found that the OS rate of the colorectal cancer patients with higher infiltration of CD8+T cells, or with higher numbers of resident CD103+CD8+T cells, or with higher ratio of CD103+CD8+T cells over total CD8+T cells in cancer tissues was significantly better than that of the patients with lower infiltration of CD8+T cells, or with lower numbers of resident CD103+CD8+T cells, or with higher ratio of CD103+CD8+T cells over total CD8+T cells in cancer tissues, respectively. Moreover, higher infiltration of CD8+T cells in colorectal cancer tissues was significantly and inversely correlated with advanced TNM stage. Higher numbers of resident CD103+CD8+T cells in colorectal cancer tissues were significantly and inversely correlated with distant metastasis status. Higher ratio of CD103+CD8+T cells over total CD8+T cells in colorectal cancer tissues was significantly and inversely correlated with age status. The COX model analysis demonstrated that higher infiltration of CD8+T cells, higher numbers of resident CD103+CD8+T cells, or higher ratio of CD103+CD8+T cells over total CD8+T cells in colorectal cancer tissues, could serve as independent prognostic predictors for colorectal cancer patients. Taken together, our present study demonstrated the density of tumor infiltrating CD8+T cells or the numbers of resident CD103+CD8+T cells in colorectal tissues could be used as an important prognostic predictor for this malignancy.


Assuntos
Antígenos CD/análise , Linfócitos T CD8-Positivos , Neoplasias Colorretais/mortalidade , Cadeias alfa de Integrinas/análise , Linfócitos do Interstício Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Antígenos CD8/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Cadeias alfa de Integrinas/metabolismo , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Subpopulações de Linfócitos T
7.
Cancer Sci ; 110(7): 2156-2165, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31099450

RESUMO

The incidence of colorectal cancer (CRC) has been on the rise, which is linked to the increasing prevalence of obesity, based on global epidemiological evidence. Although chronic inflammation is implicated in tumor development, the mechanisms underlying obesity-associated CRC remain unknown. Here, we sought to identify the inflammatory cytokines and their roles in obesity-related colorectal tumorigenesis using cytokine array analyses in a mouse model. Colorectal tumorigenesis was induced through i.p. injection of azoxymethane once a week for 6 weeks in 6-week-old female WT C57Black/6J mice and the obesity diabetes model mouse KK/TaJcl, KK-Ay/TaJcl. The formation of aberrant crypt foci and colorectal tumors were more frequent in obese mice compared with WT mice, and both serum interleukin (IL)-13 and IL-13 receptor (R) expression in the normal intestinal mucosal epithelium were significantly increased in the obese mice. Furthermore, addition of IL-13 to a human CRC cell line and a human colon organoid culture altered the phenotype of intestinal epithelial cells. Knockdown experiments further revealed that IL-13Rα1 dominantly induced mucosal proliferation. Collectively, These results suggest an association between anti-inflammatory cytokines and colorectal carcinogenesis, and provide new research directions for cancer prevention strategies. In particular, inflammation provoked by obesity, notably by increased expression of the cytokine IL-13, could play an important role in the carcinogenesis of obesity-related CRC.


Assuntos
Focos de Criptas Aberrantes/patologia , Azoximetano/efeitos adversos , Neoplasias Colorretais/patologia , Interleucina-13/sangue , Obesidade/complicações , Regulação para Cima , Focos de Criptas Aberrantes/induzido quimicamente , Focos de Criptas Aberrantes/metabolismo , Animais , Azoximetano/administração & dosagem , Proliferação de Células , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/imunologia , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/imunologia , Absorção Peritoneal , Receptores de Interleucina-13/sangue , Transdução de Sinais
8.
Gut ; 68(9): 1624-1632, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31092590

RESUMO

OBJECTIVE: In this consensus statement, an international panel of experts deliver their opinions on key questions regarding the contribution of the human microbiome to carcinogenesis. DESIGN: International experts in oncology and/or microbiome research were approached by personal communication to form a panel. A structured, iterative, methodology based around a 1-day roundtable discussion was employed to derive expert consensus on key questions in microbiome-oncology research. RESULTS: Some 18 experts convened for the roundtable discussion and five key questions were identified regarding: (1) the relevance of dysbiosis/an altered gut microbiome to carcinogenesis; (2) potential mechanisms of microbiota-induced carcinogenesis; (3) conceptual frameworks describing how the human microbiome may drive carcinogenesis; (4) causation versus association; and (5) future directions for research in the field.The panel considered that, despite mechanistic and supporting evidence from animal and human studies, there is currently no direct evidence that the human commensal microbiome is a key determinant in the aetiopathogenesis of cancer. The panel cited the lack of large longitudinal, cohort studies as a principal deciding factor and agreed that this should be a future research priority. However, while acknowledging gaps in the evidence, expert opinion was that the microbiome, alongside environmental factors and an epigenetically/genetically vulnerable host, represents one apex of a tripartite, multidirectional interactome that drives carcinogenesis. CONCLUSION: Data from longitudinal cohort studies are needed to confirm the role of the human microbiome as a key driver in the aetiopathogenesis of cancer.


Assuntos
Carcinogênese , Microbiota , Neoplasias/microbiologia , Animais , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , Carcinogênese/genética , Carcinogênese/imunologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/microbiologia , Dano ao DNA , Disbiose/complicações , Disbiose/imunologia , Disbiose/microbiologia , Microbioma Gastrointestinal , Humanos , Inflamação/microbiologia , Neoplasias/genética , Neoplasias/imunologia
9.
Cancer Treat Rev ; 76: 22-32, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31079031

RESUMO

A better knowledge of the complex interactions between cancer cells and the immune system has led to novel immunotherapy approaches. Treatment with selective anti-PD1, anti-PD-L1 and/or anti-CTLA-4 monoclonal antibodies (mAbs) has been a revolution in the therapeutic scenario of several cancer types, with the highest clinical efficacy in melanoma and in lung cancer. Colorectal cancer is one of the tumours in which immunotherapy has been shown less effective. Whereas in deficient mismatch repair (MMR) or in highly microsatellite instable (MSI-H) metastatic colorectal cancer there is clear clinical evidence for a therapeutic role of immune checkpoint inhibitors, the vast majority of patients with proficient MMR or with microsatellite stable (MSS) tumours do not benefit from immunotherapy. Defining the molecular mechanisms for immunogenicity in metastatic colorectal cancer is needed in order to develop predictive biomarkers and effective therapeutic combination strategies. A major challenge will be to identify, among the heterogeneous spectrum of this disease, those patients with specific tumour and tumour infiltrating stroma molecular and functional characteristics, that could be effectively treated with immunotherapy. In this review, we discuss the role of immune response in the context of metastatic colorectal cancer. We summarize the available clinical data with the use of anti PD-1/PD-L1 mAbs as single agents or in combination with anti CTLA-4 mAbs in MSI-H patients. Finally, we address the challenges and the potential strategies for rendering the more frequent microsatellite stable (MSS) tumours "immune-competent" and, therefore, amenable for effective immunotherapy interventions.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Neoplasias Colorretais/imunologia , Humanos , Evasão da Resposta Imune , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia
10.
Cancer Immunol Immunother ; 68(6): 1011-1024, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31053876

RESUMO

OBJECTIVE: As the development and progression of colorectal cancer (CRC) are known to be affected by the immune system, cell subsets such as T cells, natural killer (NK) cells, and natural killer T (NKT) cells are considered interesting targets for immunotherapy and clinical biomarker research. Until now, the role of systemic immune profiles in tumor progression remains unclear. In this study, we aimed to characterize the immunophenotype of circulating T cells, NK cells, and NKT-like cells in patients with CRC, and to subsequently correlate these immunophenotypes to clinical follow-up data. METHODS: Using multiparameter flow cytometry, the subset distribution and immunophenotype of T cells (CD3+CD56-), CD56dim NK cells (CD3-CD56dim), CD56bright NK cells (CD3-CD56bright), and NKT-like (CD3+CD56+) cells were investigated in peripheral blood mononuclear cell (PBMC) samples from 71 CRC patients and 19 healthy donors. RESULTS: CRC patients showed profound differences in immune cell subset distribution and their immunophenotype compared to healthy donors, as characterized by increased percentage of regulatory T cells, and reduced expression level of the natural cytotoxicity receptors NKp44 and NKp46 on both CD56dim NK cells and NKT-like cells. Finally, we showed in a multivariate analysis that above-median percentage of CD16+ NKT-like cells was independently associated with shorter disease-free survival in CRC patients. CONCLUSION: The altered phenotype of circulating immune cell subsets in CRC and its association with clinical outcome highlight the potential use of PBMC subsets as prognostic biomarkers in CRC, thereby contributing to better insight into the role of systemic immune profiles in tumor progression.


Assuntos
Neoplasias Colorretais/imunologia , Células Matadoras Naturais/imunologia , Células T Matadoras Naturais/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Complexo CD3/imunologia , Complexo CD3/metabolismo , Antígeno CD56/imunologia , Antígeno CD56/metabolismo , Neoplasias Colorretais/sangue , Neoplasias Colorretais/metabolismo , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Receptor 2 Desencadeador da Citotoxicidade Natural/imunologia , Receptor 2 Desencadeador da Citotoxicidade Natural/metabolismo , Células T Matadoras Naturais/metabolismo , Análise de Sobrevida , Linfócitos T/metabolismo , Adulto Jovem
11.
J Cancer Res Clin Oncol ; 145(7): 1785-1794, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31129768

RESUMO

PURPOSE: To investigate the associations between programmed cell death ligand-1 (PD-L1) on tumor cells (TCs) or PD-L1 on tumor-infiltrating immune cells (TIICs) and the microsatellite instability (MSI) status in colorectal cancer (CRC). METHODS: In total, 238 CRC patients were enrolled. PD-L1 expression and MSI status were studied by immunohistochemical staining and polymerase chain reaction. The χ2 test was used to compare characteristics. The Kaplan-Meier method was used for survival analysis. Cox proportional hazards models were used to determine the prognostic influence of clinicopathological factors. RESULTS: Eighteen patients (7.6%) were had MSI-high (MSI-H) CRC. The number of patients with PD-L1 expression on TCs, stromal TIICs and intraepithelial TIICs was 13 (5.5%), 64 (26.9%) and 45 (18.9%), respectively. The MSI-H phenotype was significantly associated with younger age, right sidedness, mucinous component, high grade, stromal TIICs expressing PD-L1 (P = 0.042) and intraepithelial TIICs expressing PD-L1 (P < 0.001), but not TCs expressing PD-L1. PD-L1-expressing TCs were an independent marker of poor prognosis [hazard ratio (HR) = 3.387, P = 0.003], and PD-L1-expressing stromal TIICs were an independent marker of good prognosis (HR = 0.551, P < 0.001). CONCLUSIONS: PD-L1-expressing TCs were a marker of poor prognosis; in contrast, PD-L1-expressing TIICs were a marker of good prognosis. The MSI-H phenotype was associated with the presence of PD-L1-expressing TIICs, but not of PD-L1-expressing TCs.


Assuntos
Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Neoplasias Colorretais/imunologia , Idoso , Neoplasias Colorretais/genética , Feminino , Humanos , Sistema Imunitário/patologia , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais
12.
BMC Bioinformatics ; 20(1): 264, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31117948

RESUMO

BACKGROUND: Next generation sequencing has yielded an unparalleled means of quickly determining the molecular make-up of patient tumors. In conjunction with emerging, effective immunotherapeutics for a number of cancers, this rapid data generation necessitates a paired high-throughput means of predicting and assessing neoantigens from tumor variants that may stimulate immune response. RESULTS: Here we offer NeoPredPipe (Neoantigen Prediction Pipeline) as a contiguous means of predicting putative neoantigens and their corresponding recognition potentials for both single and multi-region tumor samples. NeoPredPipe is able to quickly provide summary information for researchers, and clinicians alike, on predicted neoantigen burdens while providing high-level insights into tumor heterogeneity given somatic mutation calls and, optionally, patient HLA haplotypes. Given an example dataset we show how NeoPredPipe is able to rapidly provide insights into neoantigen heterogeneity, burden, and immune stimulation potential. CONCLUSIONS: Through the integration of widely adopted tools for neoantigen discovery NeoPredPipe offers a contiguous means of processing single and multi-region sequence data. NeoPredPipe is user-friendly and adaptable for high-throughput performance. NeoPredPipe is freely available at https://github.com/MathOnco/NeoPredPipe .


Assuntos
Antígenos de Neoplasias/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Software , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Humanos
13.
Mol Cancer ; 18(1): 64, 2019 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-30927925

RESUMO

BACKGROUND: Tumor-associated macrophages (TAMs) are major components of tumor microenvironment that frequently associated with tumor metastasis in human cancers. Circulating tumor cell (CTC), originating from primary tumor sites, is considered to be the precursors of tumor metastasis. However, the regulatory mechanism of TAMs in CTC-mediated tumor metastasis still remains unclear. METHODS: Immunohistochemical staining was used to detect the macrophages infiltration (CD68 and CD163), epithelial-mesenchymal transition (EMT) markers (E-cadherin and Vimentin) expression in serial sections of human colorectal cancer (CRC) specimens. Then, the correlations between macrophages infiltration and clinicopathologic features, mesenchymal CTC ratio, and patients' prognosis were analyzed. A co-culture assay in vitro was used to evaluate the role of TAMs on CRC EMT, migration and invasion, and ELISA, luciferase reporter assay and CHIP were performed to uncover the underlying mechanism. Furthermore, an in vivo model was carried out to confirm the effect of TAMs on mesenchymal CTC-mediated metastasis. RESULTS: Clinically, CD163+ TAMs infiltrated in invasive front was associated with EMT, mesenchymal CTC ratio, and poor prognosis in patients with CRC. CRC-conditioned macrophages regulated EMT program to enhance CRC cells migration and invasion by secreting IL6. TAMs-derived IL6 activated the JAK2/STAT3 pathway, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-506-3p in CRC cells. miR-506-3p, a key miRNA regulating FoxQ1, was downregulated in CRC cells, resulting in increased FoxQ1 expression, which in turn led to the production of CCL2 that promoted macrophage recruitment. Inhibition of CCL2 or IL6 broke this loop and reduced macrophage migration and mesenchymal CTC-mediated metastasis, respectively. CONCLUSIONS: Our data indicates that TAMs induce EMT program to enhance CRC migration, invasion, and CTC-mediated metastasis by regulating the JAK2/STAT3/miR-506-3p/FoxQ1 axis, which in turn leads to the production of CCL2 that promote macrophage recruitment, revealing a new cross-talk between immune cells and tumor cells in CRC microenvironment.


Assuntos
Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Macrófagos/patologia , Células Neoplásicas Circulantes/patologia , Microambiente Tumoral , Animais , Apoptose , Biomarcadores Tumorais , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Células Neoplásicas Circulantes/imunologia , Células Neoplásicas Circulantes/metabolismo , Prognóstico , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J BUON ; 24(1): 116-122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941959

RESUMO

PURPOSE: To investigate the effect of cytokine-induced killer cells (CIKs) immunotherapy on colorectal cancer cells and the possible mechanisms using co-culture model of CIKs and human colorectal cancer cells. METHODS: CIKs were induced by INF-γ, CD3 and recombinant human IL-2 culture system in vitro. A co-culture model of CIKs and SW480 colorectal cancer cell line was established. The proliferation, invasion and apoptosis of SW480 cells were detected by CCK-8 (cell counting kit-8), transwell assay and Hoechst staining, respectively. The contents of IL-2, IL-10, insulin-like growth factor (IGF)-ß and vascular endothelial growth factor (VEGF) in the culture medium was detected by ELISA (enzyme-linked immunosorbent assay). The expression levels of AMPK/Akt/mTOR signaling-related proteins were detected by Western blot. RESULTS: CCK-8 assay showed that the proliferative ability of co-cultured CIK+SW480 cells was remarkably lower than that of SW480 cells (p<0.05). Transwell assay showed that the number of invasive cells in co-cultured CIK+SW480 cells was less than that of SW480 cells (p<0.05). Hoechst staining showed that the apoptosis rate of co-cultured CIK+SW480 cells was higher compared with that of SW480 cells (p<0.05). Increased levels of IL-2 and IL-10 and decreased levels of IGF-ß and VEGF were found in the co-culture medium by ELISA (p<0.05). Western blot results indicated that p-AMPK and p-Akt were upregulated, whereas FoxM1 and p-mTOR were downregulated in co-cultured CIK+SW480 cells compared with SW480 cells (p<0.05). CONCLUSIONS: CIKs inhibit the proliferation and invasion of colorectal cancer cells through downregulating FoxM1 and mTOR via AMPK/Akt/mTOR pathway.


Assuntos
Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/terapia , Células Matadoras Induzidas por Citocinas/imunologia , Imunoterapia , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Apoptose/efeitos dos fármacos , Técnicas de Cocultura , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Transdução de Sinais , Células Tumorais Cultivadas
15.
Nat Commun ; 10(1): 1899, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015397

RESUMO

Nanoparticles can potentially stimulate tumour microenvironments to elicit antitumour immunity. Herein, we demonstrate effective immunotherapy of colorectal cancer via systemic delivery of an immunostimulatory chemotherapeutic combination in nanoscale coordination polymer (NCP) core-shell particles. Oxaliplatin and dihydroartemesinin have contrasting physicochemical properties but strong synergy in reactive oxygen species (ROS) generation and anticancer activity. The combined ROS generation is harnessed for immune activation to synergize with an anti-PD-L1 antibody for the treatment of murine colorectal cancer tumours. The favourable biodistribution and tumour uptake of NCPs and the absence of peripheral neuropathy allow for repeated dosing to afford 100% tumour eradication. The involvement of innate and adaptive immune systems elicit strong and long lasting antitumour immunity which prevents tumour formation when cured mice are challenged with cancer cells. The intrinsically biodegradable, well tolerated, and systemically available immunostimulatory NCP promises to enter clinical testing as an immunotherapy against colorectal cancer.


Assuntos
Adenocarcinoma/terapia , Vacinas Anticâncer/farmacologia , Neoplasias Colorretais/terapia , Fatores Imunológicos/farmacologia , Nanopartículas/administração & dosagem , Polímeros/administração & dosagem , Imunidade Adaptativa/efeitos dos fármacos , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Animais , Anticorpos Neutralizantes/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Artemisininas/farmacocinética , Artemisininas/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Vacinas Anticâncer/síntese química , Vacinas Anticâncer/farmacocinética , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Composição de Medicamentos/métodos , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/síntese química , Fatores Imunológicos/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Transplante de Neoplasias , Oxaliplatina/farmacocinética , Oxaliplatina/farmacologia , Polímeros/síntese química , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Análise de Sobrevida , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
16.
Anticancer Res ; 39(4): 1997-2005, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952743

RESUMO

BACKGROUND/AIM: Immune checkpoint inhibitors are mainly used for right-sided, microsatellite instability-high colorectal tumors. In this study, the effects of oral uracil-tegafur plus leucovorin (UFT/LV) chemotherapy on the gene expressions of four immunotherapy targets and the amounts of tumor-infiltrating lymphocytes (TILs) were investigated. PATIENTS AND METHODS: Data of 260 patients with stage II or stage III colorectal cancer were analyzed. Gene expression and amount of TILs were evaluated using real-time reverse transcription polymerase chain reaction (CRT-PCR) assay and immunohistochemical staining, respectively. RESULTS: Expression of CTLA4 and LAG3 in tumor tissues was significantly increased after UFT/LV chemotherapy, but only in left-sided tumors. The percentage of high-TIL, high-CD3 and high-FoxP3 patients in the UFT/LV group was significantly higher than that in the control group, only in left-sided tumors. CONCLUSION: The increase in TILs count, especially of CD3+ T cells and FoxP3+ regulatory T cells, after UFT/LV chemotherapy were specific to left-sided colorectal cancers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Complexo CD3/imunologia , Neoplasias Colorretais/imunologia , Fatores de Transcrição Forkhead/imunologia , Leucovorina/administração & dosagem , Linfócitos T/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Antígeno CTLA-4/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologia , Tegafur/administração & dosagem , Uracila/administração & dosagem
17.
Anticancer Res ; 39(4): 2069-2076, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952751

RESUMO

BACKGROUND/AIM: This study aimed to examine whether the semi-dry dot-blot (SDB) method can correctly identify metastasis to lymph nodes in colorectal cancer. MATERIALS AND METHODS: A total of 200 dissected lymph nodes from 83 patients with colorectal cancer who underwent surgery between November 2013 and May 2016 were examined. Each lymph node was first examined by SDB using anti-pancytokeratin antibody (AE1/AE3). Pathological Stage I/II patients with a negative reaction were further analyzed by SDB using anti-cytokeratin 20 antibody (CK-20) to detect micrometastasis or isolated tumor cells. RESULTS: The sensitivity, specificity, and accuracy of SDB using AE1/AE3 were 91.3%, 100%, and 98.0%, respectively. Five of 99 lymph nodes of pathological Stage I/II patients had a negative reaction to AE1/AE3, but were positive to CK-20, while 3 showed isolated tumor cells. CONCLUSION: The SDB is a useful diagnostic tool to detect lymph node metastases in colorectal cancer.


Assuntos
Neoplasias Colorretais/diagnóstico , Immunoblotting , Metástase Linfática/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Queratina-20/imunologia , Metástase Linfática/imunologia , Masculino , Pessoa de Meia-Idade
18.
Nat Commun ; 10(1): 1463, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30931933

RESUMO

Retinoid X receptor-alpha (RXRα) is a potent regulator of inflammatory responses; however, its therapeutic potential for inflammatory cancer remains to be explored. We previously discovered that RXRα is abnormally cleaved in tumor cells and tissues, producing a truncated RXRα (tRXRα). Here, we show that transgenic expression of tRXRα in mice accelerates the development of colitis-associated colon cancer (CAC). The tumorigenic effect of tRXRα is primarily dependent on its expression in myeloid cells, which results in interleukin-6 (IL-6) induction and STAT3 activation. Mechanistic studies reveal an extensive interaction between tRXRα and TRAF6 in the cytoplasm of macrophages, leading to TRAF6 ubiquitination and subsequent activation of the NF-κB inflammatory pathway. K-80003, a tRXRα modulator derived from nonsteroidal anti-inflammatory drug (NSAID) sulindac, suppresses the growth of tRXRα-mediated colorectal tumor by inhibiting the NF-κB-IL-6-STAT3 signaling cascade. These results provide new insight into tRXRα action and identify a promising tRXRα ligand for treating CAC.


Assuntos
Carcinogênese/genética , Colite/genética , Neoplasias Colorretais/genética , Interleucina-6/imunologia , Receptor X Retinoide alfa/genética , Fator de Transcrição STAT3/imunologia , Animais , Carcinogênese/imunologia , Colite/imunologia , Colite Ulcerativa/imunologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/metabolismo , Neoplasias Colorretais/imunologia , Meios de Cultivo Condicionados , Modelos Animais de Doenças , Células HCT116 , Humanos , Inflamação , Macrófagos/imunologia , Camundongos , NF-kappa B/imunologia , Receptor X Retinoide alfa/imunologia , Transdução de Sinais , Sulindaco/análogos & derivados , Sulindaco/farmacologia , Fator 6 Associado a Receptor de TNF/imunologia
20.
Nat Rev Gastroenterol Hepatol ; 16(6): 361-375, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30886395

RESUMO

Following initial successes in melanoma treatment, immunotherapy has rapidly become established as a major treatment modality for multiple types of solid cancers, including a subset of colorectal cancers (CRCs). Two programmed cell death 1 (PD1)-blocking antibodies, pembrolizumab and nivolumab, have shown efficacy in patients with metastatic CRC that is mismatch-repair-deficient and microsatellite instability-high (dMMR-MSI-H), and have been granted accelerated FDA approval. In contrast to most other treatments for metastatic cancer, immunotherapy achieves long-term durable remission in a subset of patients, highlighting the tremendous promise of immunotherapy in treating dMMR-MSI-H metastatic CRC. Here, we review the clinical development of immune checkpoint inhibition in CRC leading to regulatory approvals for the treatment of dMMR-MSI-H CRC. We focus on new advances in expanding the efficacy of immunotherapy to early-stage CRC and CRC that is mismatch-repair-proficient and has low microsatellite instability (pMMR-MSI-L) and discuss emerging approaches for targeting the immune microenvironment, which might complement immune checkpoint inhibition.


Assuntos
Neoplasias Colorretais/terapia , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Neoplasias Colorretais/imunologia , Humanos , Terapia de Alvo Molecular/métodos , Resultado do Tratamento
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