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1.
Anticancer Res ; 41(10): 5157-5163, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593467

RESUMO

BACKGROUND/AIM: Adjuvant platinum-based chemotherapy (APC) has been the standard of care for patients with non-small-cell lung cancer (NSCLC) who have undergone complete pulmonary resection. This study analyzed the clinical and prognostic significance of immunonutritional indices in NSCLC patients receiving APC. PATIENTS AND METHODS: We retrospectively reviewed 110 patients from 2008 to 2016. Three immunonutritional indices were calculated: neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI). RESULTS: The median age was 64 years, and 66 patients were males. Each index showed a significant correlation with primary tumor length. NLR and PLR were significantly correlated with vascular invasion. Prognostic analyses revealed that each index was significantly correlated with postoperative recurrence-free survival (RFS) and overall survival (OS). On multivariate analyses, PNI was an independent predictor of RFS and OS. CONCLUSION: Host immunonutritional status may have a significant effect on the postoperative prognosis of NSCLC in patients receiving APC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Plaquetas/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linfócitos/patologia , Neutrófilos/patologia , Estado Nutricional , Compostos Organoplatínicos/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
2.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360996

RESUMO

ß-Casomorphin-7 (BCM) is a degradation product of ß-casein, a milk component, and has been suggested to affect the immune system. However, its effect on mucosal immunity, especially anti-tumor immunity, in cancer-bearing individuals is not clear. We investigated the effects of BCM on lymphocytes using an in vitro system comprising mouse splenocytes, a mouse colorectal carcinogenesis model, and a mouse orthotopic colorectal cancer model. Treatment of mouse splenocytes with BCM in vitro reduced numbers of cluster of differentiation (CD) 20+ B cells, CD4+ T cells, and regulatory T cells (Tregs), and increased CD8+ T cells. Administration of BCM and the CD10 inhibitor thiorphan (TOP) to mice resulted in similar alterations in the lymphocyte subsets in the spleen and intestinal mucosa. BCM was degraded in a concentration- and time-dependent manner by the neutral endopeptidase CD10, and the formed BCM degradation product did not affect the lymphocyte counts. Furthermore, degradation was completely suppressed by TOP. In the azoxymethane mouse colorectal carcinogenesis model, the incidence of aberrant crypt foci, adenoma, and adenocarcinoma was reduced by co-treatment with BCM and TOP. Furthermore, when CT26 mouse colon cancer cells were inoculated into the cecum of syngeneic BALB/c mice and concurrently treated with BCM and TOP, infiltration of CD8+ T cells was promoted, and tumor growth and liver metastasis were suppressed. These results suggest that by suppressing the BCM degradation system, the anti-tumor effect of BCM is enhanced and it can suppress the development and progression of colorectal cancer.


Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Endorfinas/uso terapêutico , Linfócitos/imunologia , Fragmentos de Peptídeos/uso terapêutico , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Animais , Linhagem Celular Tumoral , Células Cultivadas , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Endorfinas/farmacologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Linfócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Fragmentos de Peptídeos/farmacologia , Inibidores de Proteases/farmacologia , Baço/citologia , Baço/imunologia , Tiorfano/farmacologia
3.
Am J Physiol Gastrointest Liver Physiol ; 321(2): G213-G222, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34231392

RESUMO

Advances in -omics analyses have tremendously enhanced our understanding of the role of the microbiome in human health and disease. Most research is focused on the bacteriome, but scientists have now realized the significance of the virome and microbial dysbiosis as well, particularly in noninfectious diseases such as cancer. In this review, we summarize the role of mycobiome in tumorigenesis, with a dismal prognosis, and attention to pancreatic ductal adenocarcinoma (PDAC). We also discuss bacterial and mycobial interactions to the host's immune response that is prevalently responsible for resistance to cancer therapy, including immunotherapy. We reported that the Malassezia species associated with scalp and skin infections, colonize in human PDAC tumors and accelerate tumorigenesis via activating the C3 complement-mannose-binding lectin (MBL) pathway. PDAC tumors thrive in an immunosuppressive microenvironment with desmoplastic stroma and a dysbiotic microbiome. Host-microbiome interactions in the tumor milieu pose a significant threat in driving the indolent immune behavior of the tumor. Microbial intervention in multimodal cancer therapy is a promising novel approach to modify an immunotolerant ("cold") tumor microenvironment to an immunocompetent ("hot") milieu that is effective in eliminating tumorigenesis.


Assuntos
Adenocarcinoma/microbiologia , Carcinogênese , Micobioma/imunologia , Neoplasias Pancreáticas/microbiologia , Adenocarcinoma/imunologia , Adenocarcinoma/terapia , Animais , Humanos , Imunoterapia/métodos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/terapia
4.
Clin Immunol ; 229: 108797, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34273585

RESUMO

The global obesity epidemic is contributing to increased prevalence of diseases fuelled by chronic inflammation, including cancer. Oesophageal adenocarcinoma (OAC) is an obesity-associated malignancy with increasing prevalence, dismal prognosis, and severely dysregulated immune processes. We previously reported that αß T cells migrate to omentum and liver in OAC and contribute to inflammation in these tissues. Here, we assessed the tissue distribution and phenotype of gamma/delta (γδ) T cells in the blood, omentum, liver and tumour of OAC patients. Our data show that the Vδ1 and Vδ3 subsets of γδ T cells are most prevalent in omentum and liver of OAC patients. Furthermore, γδ T cells are predominantly pro-inflammatory in these tissues, and co-express IFN-γ and IL-17. Moreover, γδ T cells exhibit cytotoxic capabilities in OAC omentum and liver. This study provides the first indication that γδ T cells contribute to obesity-associated inflammation in OAC and might be exploited therapeutically.


Assuntos
Adenocarcinoma/imunologia , Neoplasias Esofágicas/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Subpopulações de Linfócitos T/imunologia , Adenocarcinoma/etiologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Degranulação Celular , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/patologia , Feminino , Humanos , Imunofenotipagem , Inflamação/complicações , Interferon gama/metabolismo , Interleucina-17/metabolismo , Fígado/imunologia , Fígado/patologia , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Omento/imunologia , Omento/patologia , Receptores CCR6/metabolismo , Subpopulações de Linfócitos T/patologia , Subpopulações de Linfócitos T/fisiologia , Distribuição Tecidual
5.
J Immunol ; 207(3): 771-776, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34290103

RESUMO

Tumor-infiltrating regulatory T cells (Tregs) have been extensively studied as therapeutic targets. However, not all infiltrating T cells exert their functions equally, presumably because of their heterogeneity and substantial turnover in tissues. In this study, we hypothesized that intertissue migration underlies the functional heterogeneity of Tregs. To test this, we applied in vivo photolabeling to examine single-cell diversity of immunosuppressive molecules in mouse Tregs migrating to, remaining in, and emigrating from MC38 tumors. Neuropilin-1 (Nrp1) expression was inversely correlated with that of six other molecules associated with Treg function. Unsupervised clustering analyses revealed that clusters containing Tregs that were retained in tumors expressed high levels of the six functional molecules but not of Nrp1. However, these clusters represented only half of the Tregs migrating to the tumor, suggesting evolving heterogeneity of tumor-infiltrating Tregs. Thus, we propose progressive pathways of Treg activation and migration between tumors and draining lymph nodes.


Assuntos
Adenocarcinoma/imunologia , Neoplasias do Colo/imunologia , Fatores de Transcrição Forkhead/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Análise de Célula Única/métodos , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Humanos , Ativação Linfocitária , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais , Neuropilina-1/genética , Neuropilina-1/metabolismo , Fenótipo
6.
Nat Commun ; 12(1): 4536, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315872

RESUMO

Despite the substantial impact of post-translational modifications on programmed cell death 1 ligand 1 (PD-L1), its importance in therapeutic resistance in pancreatic cancer remains poorly defined. Here, we demonstrate that never in mitosis gene A-related kinase 2 (NEK2) phosphorylates PD-L1 to maintain its stability, causing PD-L1-targeted pancreatic cancer immunotherapy to have poor efficacy. We identify NEK2 as a prognostic factor in immunologically "hot" pancreatic cancer, involved in the onset and development of pancreatic tumors in an immune-dependent manner. NEK2 deficiency results in the suppression of PD-L1 expression and enhancement of lymphocyte infiltration. A NEK binding motif (F/LXXS/T) is identified in the glycosylation-rich region of PD-L1. NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen. NEK2 inhibition thereby sensitizes PD-L1 blockade, synergically enhancing the anti-pancreatic cancer immune response. Together, the present study proposes a promising strategy for improving the effectiveness of pancreatic cancer immunotherapy.


Assuntos
Antígeno B7-H1/metabolismo , Imunidade , Quinases Relacionadas a NIMA/antagonistas & inibidores , Neoplasias Pancreáticas/imunologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Modelos Biológicos , Quinases Relacionadas a NIMA/deficiência , Quinases Relacionadas a NIMA/genética , Quinases Relacionadas a NIMA/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosforilação , Fosfosserina/metabolismo , Prognóstico , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Estabilidade Proteica , Proteólise , Ubiquitinação
7.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198548

RESUMO

Inflammation in the tumor microenvironment has been shown to promote disease progression in pancreatic ductal adenocarcinoma (PDAC); however, the role of macrophage metabolism in promoting inflammation is unclear. Using an orthotopic mouse model of PDAC, we demonstrate that macrophages from tumor-bearing mice exhibit elevated glycolysis. Macrophage-specific deletion of Glucose Transporter 1 (GLUT1) significantly reduced tumor burden, which was accompanied by increased Natural Killer and CD8+ T cell activity and suppression of the NLRP3-IL1ß inflammasome axis. Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.


Assuntos
Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Citoproteção , Glicólise , Macrófagos/metabolismo , Neoplasias Pancreáticas/patologia , Adenocarcinoma/imunologia , Animais , Carcinoma Ductal Pancreático/imunologia , Proliferação de Células/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transportador de Glucose Tipo 1/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Hidroxibenzoatos/farmacologia , Inflamação/patologia , Interleucina-1beta/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias Pancreáticas/imunologia , Análise de Sobrevida , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Carga Tumoral/efeitos dos fármacos
8.
Aging (Albany NY) ; 13(13): 17548-17567, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233297

RESUMO

The C-X-C motif (CXC) chemokines are a family of chemotactic molecules that have been identified as potential prognostic markers and prospective therapeutic targets for many kinds of cancer types. Increasing evidence shows that CXC chemokines are associated with the progression of colorectal cancer (CRC); however, the correlations of CXC chemokines with prognostic and immune infiltrates in CRC remain to be clarified. In this study, we analyzed the mRNA expression level, prognostic data and immune infiltrates of CXC chemokines in CRC patients from the Gene Expression Profiling Interactive Analysis, Oncomine, cBioPortal and databases using GeneMANIA, STRING, DAVID 6.8, and TIMER. Our results showed that CXCL1/2/3/4/5/8/9/10/11/13/14/16 were significantly overexpressed in CRC tissues. Furthermore, expression of CXCL1/2/3/9/10/11 was associated with tumor stage in CRC. A significant association was also identified between the co-expression of CXCL16 with EGFR, KRAS and NRAS. In addition, the survival analysis suggested that high CXCL2/3/8/9/10/11/14 expression is correlated with clinical outcomes of CRC patients. Moreover, a significant association was observed between the CXCL8/9/10/11 expression and immune infiltration in colonic and rectal adenocarcinoma. Overall, CXC chemokines are not only implicated as prognostic biomarkers for CRC patients, but may also influence the immune status of CRC tissues.


Assuntos
Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Quimiocinas CXC/análise , Quimiocinas CXC/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Biomarcadores Tumorais/análise , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Prognóstico , Estudos Prospectivos , Análise de Sobrevida
9.
Aging (Albany NY) ; 13(13): 17734-17767, 2021 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-34247148

RESUMO

Limited progress has been made in the treatment of gastric adenocarcinoma (GAC) in recent years, but the potential of immunotherapy in GAC is worthy of consideration. The purpose of this study was to develop a reliable, personalized signature based on immune genes to predict the prognosis of GAC. Here, we identified two groups of patients with significantly different prognoses by performing unsupervised clustering analysis of The Cancer Genome Atlas (TCGA) database based on 881 immune genes. The immune signature was constructed with a training set composed of 350 GAC samples from the TCGA and subsequently validated with 431 samples from GSE84437, 432 samples from GSE26253, and 145 GAC samples from real-time quantitative reverse transcription polymerase chain reaction data. This classification system can also be used to predict prognosis in different clinical subgroups. Further analysis suggested that high-risk patients were characterized by low immune scores, distinctive immune cell proportions, different immune checkpoint profiles, and a low tumor mutational burden. Ultimately, the signature was identified as an independent prognostic factor. In general, the signature can accurately predict recurrence and overall survival in patients with GAC and may serve as a powerful prognostic tool to further optimize cancer immunotherapy.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/imunologia , Imunidade/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Análise por Conglomerados , Biologia Computacional , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Reação em Cadeia da Polimerase , Medicina de Precisão , Valor Preditivo dos Testes , Prognóstico , Análise de Sobrevida
10.
J Immunol ; 207(4): 1200-1210, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34321227

RESUMO

Esophagogastric adenocarcinomas (EAC) are obesity-associated malignancies underpinned by severe immune dysregulation and inflammation. Our previous work indicates that NK cells migrate to EAC omentum, where they undergo phenotypic and functional alterations and apoptosis. In this study, we investigate whether such erroneous chemotaxis to omentum is paralleled by compromised NK cell infiltration of EAC patient tumor and examine the role of the inflammatory chemokine fractalkine in shaping the NK cell-mediated response. Our data show diminished NK cell frequencies in EAC tumor compared with those in the circulation and reveal that intratumoral NK cell frequencies decline as visceral obesity increases in EAC patients. Our in vitro findings demonstrate that antagonism of fractalkine receptor CX3CR1 significantly reduces NK cell migration to EAC patient-derived, omental adipose tissue-conditioned media, but not toward tumor-conditioned media. These data suggest fractalkine is a key driver of NK cell chemotaxis to omentum but has a lesser role in NK cell homing to tumor in EAC. We propose that this may offer a novel therapeutic strategy to limit NK cell depletion in the omentum of obese EAC patients, and our data suggest the optimal timing for CX3CR1 antagonism is after neoadjuvant chemoradiotherapy. Our functional studies demonstrate that fractalkine induces the conversion from CX3CR1+CD27- to CX3CR1-CD27+ NK cells and increases their IFN-γ and TNF-α production, indicative of its role in shaping the dominant NK cell phenotype in EAC omentum. This study uncovers crucial and potentially druggable pathways underpinning NK cell dysfunction in obesity-associated cancer and provides compelling insights into fractalkine's diverse biological functions.


Assuntos
Quimiocina CX3CL1/imunologia , Quimiotaxia/imunologia , Células Matadoras Naturais/imunologia , Obesidade/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Adenocarcinoma/imunologia , Tecido Adiposo/imunologia , Movimento Celular/imunologia , Neoplasias Esofágicas/imunologia , Feminino , Humanos , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Receptores de Quimiocinas/imunologia , Neoplasias Gástricas/imunologia
11.
Aging (Albany NY) ; 13(12): 16024-16042, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34133324

RESUMO

Prostate adenocarcinoma is one of the leading adult malignancies. Identification of multiple causative biomarkers is necessary and helpful for determining the occurrence and prognosis of prostate adenocarcinoma. We aimed to identify the potential prognostic genes in the prostate adenocarcinoma microenvironment and to estimate the causal effects simultaneously. We obtained the gene expression data of prostate adenocarcinoma from TCGA project and identified the differentially expressed genes based on immune-stromal components. Among these genes, 68 were associated with biochemical recurrence at 3 years after prostatectomy in prostate adenocarcinoma. After adjusting for the minimal sets of confounding covariates, 14 genes (TNFRSF4, ZAP70, ERMN, CXCL5, SPINK6, SLC6A18, CHRM2, TG, CLLU1OS, POSTN, CTSG, NETO1, CEACAM7, and IGLV3-22) related to the microenvironment were identified as prognostic biomarkers using the targeted maximum likelihood estimation. Both the average and individual causal effects were obtained to measure the magnitude of the effect. CIBERSORT and gene set enrichment analyses showed that these prognostic genes were mainly associated with immune responses. POSTN and NETO1 were correlated with androgen receptor expression, a main driver of prostate adenocarcinoma progression. Finally, five genes were validated in another prostate adenocarcinoma cohort (GEO: GSE70770). These findings might lead to the improved prognosis of prostate adenocarcinoma.


Assuntos
Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Biomarcadores Tumorais/metabolismo , Recidiva Local de Neoplasia/patologia , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Microambiente Tumoral , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Fatores de Confusão Epidemiológicos , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Receptores Androgênicos/metabolismo , Reprodutibilidade dos Testes , Células Estromais/metabolismo , Microambiente Tumoral/genética
12.
Front Immunol ; 12: 651056, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122409

RESUMO

The incidence of adenocarcinoma of the esophagogastric junction (AEG) has markedly increased worldwide. However, the precise etiology of AEG is still unclear, and the therapeutic options thus remain limited. Growing evidence has implicated long non-coding RNAs (lncRNAs) in cancer immunomodulation. This study aimed to examine the tumor immune infiltration status and assess the prognostic value of immune-related lncRNAs in AEG. Using the ESTIMATE method and single-sample GSEA, we first evaluated the infiltration level of 28 immune cell types in AEG samples obtained from the TCGA dataset (N=201). Patients were assigned into high- and low-immune infiltration subtypes based on the immune cell infiltration's enrichment score. GSEA and mutation pattern analysis revealed that these two immune infiltration subtypes had distinct phenotypes. We identified 1470 differentially expressed lncRNAs in two immune infiltration subtypes. From these differentially expressed lncRNAs, six prognosis-related lncRNAs were selected using the Cox regression analysis. Subsequently, an immune risk signature was constructed based on combining the values of the six prognosis-associated lncRNAs expression levels and multiple regression coefficients. To determine the risk model's prognostic capability, we performed a series of survival analyses with Kaplan-Meier methods, Cox proportional hazards regression models, and the area under receiver operating characteristic (ROC) curve. The results indicated that the immune-related risk signature could be an independent prognostic factor with a significant predictive value in patients with AEG. Furthermore, the immune-related risk signature can effectively predict the response to immunotherapy and chemotherapy in AEG patients. In conclusion, the proposed immune-related lncRNA prognostic signature is reliable and has high survival predictive value for patients with AEG and is a promising potential biomarker for immunotherapy.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/genética , Regulação Neoplásica da Expressão Gênica/imunologia , RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/genética , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Conjuntos de Dados como Assunto , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/imunologia , Junção Esofagogástrica/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Prognóstico , Medição de Risco/métodos , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
13.
Theranostics ; 11(14): 6668-6681, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093846

RESUMO

Background: Newly emerging cancer immunotherapy has led to significant progress in cancer treatment; however, its efficacy is limited in solid tumors since the majority of them are "cold" tumors. Oncolytic viruses, especially when properly armed, can directly target tumor cells and indirectly modulate the tumor microenvironment (TME), resulting in "hot" tumors. These viruses can be applied as a cancer immunotherapy approach either alone or in combination with other cancer immunotherapies. Cytokines are good candidates to arm oncolytic viruses. IL-23, an IL-12 cytokine family member, plays many roles in cancer immunity. Here, we used oncolytic vaccinia viruses to deliver IL-23 variants into the tumor bed and explored their activity in cancer treatment on multiple tumor models. Methods: Oncolytic vaccinia viruses expressing IL-23 variants were generated by homologue recombination. The characteristics of these viruses were in vitro evaluated by RT-qPCR, ELISA, flow cytometry and cytotoxicity assay. The antitumor effects of these viruses were evaluated on multiple tumor models in vivo and the mechanisms were investigated by RT-qPCR and flow cytometry. Results: IL-23 prolonged viral persistence, probably mediated by up-regulated IL-10. The sustainable IL-23 expression and viral oncolysis elevated the expression of Th1 chemokines and antitumor factors such as IFN-γ, TNF-α, Perforin, IL-2, Granzyme B and activated T cells in the TME, transforming the TME to be more conducive to antitumor immunity. This leads to a systemic antitumor effect which is dependent on CD8+ and CD4+ T cells and IFN-γ. Oncolytic vaccinia viruses could not deliver stable IL-23A to the tumor, attributed to the elevated tristetraprolin which can destabilize the IL-23A mRNA after the viral treatment; whereas vaccinia viruses could deliver membrane-bound IL-23 to elicit a potent antitumor effect which might avoid the possible toxicity normally associated with systemic cytokine exposure. Conclusion: Either secreted or membrane-bound IL-23-armed vaccinia virus can induce potent antitumor effects and IL-23 is a candidate cytokine to arm oncolytic viruses for cancer immunotherapy.


Assuntos
Adenocarcinoma/terapia , Neoplasias do Colo/terapia , Imunoterapia/métodos , Interleucina-23/farmacologia , Vírus Oncolíticos/genética , Microambiente Tumoral/imunologia , Vírus Vaccinia/genética , Adenocarcinoma/imunologia , Adenocarcinoma/virologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Neoplasias do Colo/imunologia , Neoplasias do Colo/virologia , Modelos Animais de Doenças , Feminino , Vetores Genéticos , Granzimas/metabolismo , Humanos , Interferon gama/metabolismo , Interleucina-12/metabolismo , Interleucina-2/metabolismo , Interleucina-23/genética , Interleucina-23/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Vírus Oncolíticos/metabolismo , Perforina/metabolismo , Microambiente Tumoral/genética , Fator de Necrose Tumoral alfa/metabolismo , Vírus Vaccinia/metabolismo
14.
Medicine (Baltimore) ; 100(19): e25773, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34106609

RESUMO

RATIONALE: Anti-PD-1 antibody is the standard therapy for treatment-resistant gastric cancer, but only a limited number of patients respond. Additionally, cases of hyper-progressive disease (HPD) in which tumor growth accelerates after anti-PD-1 antibody administration have been reported; however, the biological mechanism has not been elucidated. PATIENT CONCERNS: In the present case, metastatic gastric cancer was treated with the anti-PD-1 antibody, nivolumab, as third-line treatment. DIAGNOSIS: After the initiation of nivolumab therapy, a rapidly enlarging para-aortic lymph nodes were observed leading to the diagnosis of HPD. INTERVENTIONS: Multiplex immunohistochemistry was used to examine immune cells infiltrating in the primary tumor and in liver metastasis which were obtained before nivolumab treatment, and in lymph node metastasis which presented with HPD after nivolumab therapy. OUTCOMES: In the primary tumor, helper T (Th) cells, cytotoxic T lymphocytes (CTLs), regulatory T (Treg) cells, and PD-L1-negative macrophages were observed. On the other hand, in metastatic lymph nodes presenting with HPD, PD-L1-positive macrophages prominently increased, while Treg cells, CTLs, and Th cells decreased. PD-L1 expression was not observed in gastric cancer cells among the three specimens. LESSONS: The findings suggest the possibility that PD-L1-positive M2 macrophage might contribute to acceleration of tumor growth with anti-PD-1 therapy in the present case.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Nivolumabe/efeitos adversos , Neoplasias Gástricas/tratamento farmacológico , Macrófagos Associados a Tumor/efeitos dos fármacos , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/antagonistas & inibidores , Progressão da Doença , Evolução Fatal , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia
15.
Aging (Albany NY) ; 13(12): 16637-16655, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162762

RESUMO

BACKGROUND: Stomach adenocarcinoma (STAD) is one of the most prevalent malignances and ranks fifth in incidence and third in cancer-related death among all malignances. The prognosis of STAD is poor. The circadian clock is regulated by interlocked transcriptional-translational feedback loops that orchestrate circadian rhythms in some biological processes, including the immune response and metabolism. However, the association between core circadian clock genes and STAD patient prognosis is unclear. MATERIALS AND METHODS: In our study, bioinformatics methods were performed to explore the expression and prognostic value of core circadian clock genes in STAD and their association with immune infiltration. RESULTS: The mRNA levels of CLOCK, CRY1 and NR1D1 were upregulated, while the mRNA levels of CRY2, PER1, PER3 and RORA were downregulated in STAD tissues compared with normal tissues. Core circadian clock genes exert promoting or inhibiting effects on certain cancer-related hallmark pathways, including the DNA damage response, cell cycle, apoptosis and RAS/MAPK pathways. Moreover, core circadian clock genes were linked to drug sensitivity or drug resistance. Prognosis analysis revealed that high expression of PER1 and NR1D1 was associated with poor overall survival, progression-free survival, and disease-free survival rates in STAD patients. Validation analysis further confirmed our result. Immune infiltration analysis demonstrated that the expression of ICOSLG and CD70 was significantly correlated with immune cells, immune biomarkers, chemokines and their receptors. CONCLUSIONS: Our results suggest that NR1D1 and PER1 are prognostic biomarkers and are associated with immune infiltration in STAD.


Assuntos
Adenocarcinoma/imunologia , Adenocarcinoma/fisiopatologia , Relógios Circadianos/fisiologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/fisiopatologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Relógios Circadianos/efeitos dos fármacos , Relógios Circadianos/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Mutação/genética , Prognóstico , Reprodutibilidade dos Testes , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Análise de Sobrevida
16.
Anticancer Res ; 41(5): 2543-2552, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952482

RESUMO

BACKGROUND/AIM: Maspin is a tumor-suppressor protein expressed in >90% of pancreatic ductal adenocarcinoma (PDAC) cases. We aimed to assess the prognostic value of subcellular localization of maspin. PATIENTS AND METHODS: Ninety-two resected PDAC specimens were immunohistochemically analyzed. Cytoplasmic-only expression observed in >10% of the tumor was defined as maspin-positive. RESULTS: The maspin-positive status (21.7%) was inversely correlated with well-differentiated histological type and indicated a shorter recurrence-free survival (RFS) and overall survival (OS). Cox's multivariate analysis showed that maspin-positive status was an independent factor for shorter RFS and OS. Maspin was localized to cytoplasm in AsPC-1 cells, but to both nucleus and cytoplasm in BxPC-3 cells. In AsPC-1 cells, cell invasion was significantly reduced in response to maspin suppression via transfection with siRNA targeting maspin, whereas no reduction was observed in BxPC-3 cells. CONCLUSION: Cytoplasmic-only expression of maspin could be an independent unfavorable prognostic indicator for patients with PDAC.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Serpinas/genética , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Idoso , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Citoplasma/efeitos dos fármacos , Citoplasma/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/imunologia , Serpinas/imunologia
17.
Cancer Treat Rev ; 98: 102219, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33993033

RESUMO

With an incidence that is constantly rising, oesophageal adenocarcinoma (OAC) is becoming an increasing health burden worldwide. Although significant advances in treatment regimens have improved patient outcomes, survival rates for this deadly cancer remain unsatisfactory. This highlights the need to improve current therapeutic approaches and develop novel therapeutic strategies for treating OAC patients. The advent of immunotherapy has revolutionised treatment across a range of malignancies, however outcomes in OAC show modest results. The inherent resistance of OAC to treatment reflects the complex genomic landscape of this cancer, which displays a lack of ubiquitous driver mutations and large-scale genomic alterations along with high tumour and immune heterogeneity. Research into the immune landscape of OAC is limited, and elucidation of the mechanisms surrounding the immune responses to this complex cancer will result in improved therapeutic approaches. This review explores what is known about the immuno-biology of OAC and explores promising therapeutic avenues that may improve responses to immunotherapeutic regimens.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/imunologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/imunologia , Imunoterapia/métodos , Adenocarcinoma/patologia , Animais , Neoplasias Esofágicas/patologia , Humanos
18.
Methods Mol Biol ; 2255: 159-169, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34033102

RESUMO

Cytotoxic T cell-induced cell death is well documented. Cytotoxic T cell releases various cytolytic proteins. The cytolytic proteins induce target cell death. T cell-induced cell death can be measured by the lytic assay. One of the well-known lytic assays uses radioactive tracer, Chromium-51 (51Cr), and detects the amount of 51Cr released from target cells. This assay can detect cell death and the efficiency of the T cell-induced cell death by coculture effector cells (T cells) and target cells. This assay can determine the kinetics of the cell lysis. The issue of this approach is the use of radioactive material. This chapter describes measuring T cell-induced cell death by determining the epigenetic remodeling and the release of cytolytic proteins. Determine the efficiency of T cell-induced cell death by using a flow cytometry-based detection method.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Radioisótopos de Cromo/análise , Neoplasias do Colo/patologia , Testes Imunológicos de Citotoxicidade/métodos , Citometria de Fluxo/métodos , Linfoma de Células B/patologia , Linfócitos T Citotóxicos/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Morte Celular , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Camundongos , Células Tumorais Cultivadas
19.
Medicine (Baltimore) ; 100(21): e26170, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032778

RESUMO

ABSTRACT: To identify prognostic tumor-infiltrating immune cells of endometrial adenocarcinoma.The gene expression profiles of endometrial adenocarcinoma were downloaded from the Cancer Genome Atlas (TCGA). The abundance of tumor-infiltrating immune cells in endometrial adenocarcinoma samples was calculated by CIBERSORT algorithm. Kaplan-Meier analysis was used to identify prognostic tumor-infiltrating immune cells.This study identified 22 kinds of tumor-infiltrating immune cells. Macrophages M0 and CD8 T cells were prognostic factors of endometrial adenocarcinoma. The abundance of macrophages M0 (P = .038) was significantly correlated with better prognosis of endometrial adenocarcinoma. In contrast, the abundance of CD8 T cells (P = .049) was associated with poor prognosis of endometrial adenocarcinoma.Tumor-infiltrati macrophages M0 and CD8 T cells were prognostic factors of endometrial adenocarcinoma.


Assuntos
Adenocarcinoma/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias do Endométrio/imunologia , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/imunologia , Algoritmos , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Prognóstico , Microambiente Tumoral
20.
Immunology ; 163(4): 512-520, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33838058

RESUMO

CD4+ regulatory T (Treg) cells, dependent upon the transcription factor Foxp3, contribute to tumour immunosuppression but are also required for immune homeostasis. There is interest in developing therapies that selectively target the immunosuppressive function of Treg cells within tumours without disrupting their systemic anti-inflammatory function. High levels of expression of chemokine (C-C motif) receptor 8 (CCR8) discriminate Treg cells within tumours from those found in systemic lymphoid tissues. It has recently been proposed that disruption of CCR8 function using blocking anti-CCR8 antibodies results in reduced accumulation of Treg cells within tumours and disruption of their immunosuppressive function. Here, using Ccr8-/- mice, we show that CCR8 function is not required for Treg cell accumulation or immunosuppression in the context of syngeneic MC38 colorectal adenocarcinoma and B16 melanoma tumours. We observed high levels of CCR8 expression on tumour-infiltrating Treg cells which were abolished in Ccr8-/- mice. High levels of CCR8 marked cells with high levels of suppressive function. However, whereas systemic ablation of Treg cells resulted in strikingly diminished tumour burden, growth of subcutaneously implanted tumours was unaffected by systemic CCR8 loss. Consistently, we observed minimal impact of systemic CCR8 ablation on the frequency, phenotype and function of tumour-infiltrating Treg cells and conventional T (Tconv) function. These findings suggest that CCR8 is not required for Treg cell accumulation and immunosuppressive function within tumours and that depletion of CCR8+ Treg cells rather than blockade of CCR8 function is a more promising avenue for selective immunotherapy.


Assuntos
Adenocarcinoma/imunologia , Neoplasias Colorretais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Receptores CCR8/metabolismo , Neoplasias Cutâneas/imunologia , Linfócitos T Reguladores/imunologia , Animais , Fatores de Transcrição Forkhead/metabolismo , Humanos , Tolerância Imunológica , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CCR8/genética
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