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BACKGROUND: To comprehensively analyze the clinical significance of Immune Checkpoint-Related Genes (ICRGs) in Pancreatic Adenocarcinoma (PAAD). METHOD: PAAD tissues and normal pancreatic tissues were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, and 283 ICRGs were integrated by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome datasets. Unsupervised clustering was used to obtain potential ICRGs-based PAAD subtypes. Wilcoxon test was performed to screen Differentially Expressed ICRGs (DEICRGs), while cox regression analyses were utilized to identify prognosis-related ICRGs and clinicopathological factors, and construct the corresponding models. The Tumor Immune Microenvironment (TIME) was evaluated. Moreover, the authors performed enrichment analysis, Gene Set Enrichment Analysis (GSEA), and transcription factor regulatory networks to realize underlying mechanisms. RESULTS: Three ICRGs-based PAAD subtypes were identified, and they were associated with three ESTIMATE scores, a Tumor Microenvironment (TMB) score, 14 therapeutic immune checkpoints, and infiltration levels of seven immune cells. On top of that, the authors constructed two signatures based on DEICRGs to predict the Overall Survival (OS) (Area Under the ROC Curve [AUC: 0.741∼0.778]) and Progression-Free Survival (PFS) (AUC: 0.746∼0.831) of patients. Two nomograms were established by combining clinical variables and signatures. In addition, the authors found higher infiltration of naïve B cells and CD8+ T-cells in low-risk PAAD patients, and higher infiltration of suppressive immune cells and cancer-related signaling pathways in high-risk PAAD patients. CONCLUSION: The present study suggested that ICRGs were associated with TIME formation and prognosis of PAAD patients, which may serve as novel clinical biomarkers and therapeutic targets.

Asunto(s)

Adenocarcinoma , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Masculino , Femenino , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Regulación Neoplásica de la Expresión Génica/genética , Proteínas de Punto de Control Inmunitario/genética , Anciano

RESUMEN

INTRODUCTION: Pancreatic adenocarcinoma is an extremely aggressive neoplasm, with many challenges to be overcome in order to achieve a truly effective treatment. It is characterized by a mostly immunosuppressed environment, with dysfunctional immune cells and active immunoinhibitory pathways that favor tumor evasion and progression. Thus, the study and understanding of the tumor microenvironment and the various cells subtypes and their functional capacities are essential to achieve more effective treatments, especially with the use of new immunotherapeutics. METHODS: Seventy cases of pancreatic adenocarcinoma divided into two groups 43 with resectable disease and 27 with unresectable disease were analyzed using immunohistochemical methods regarding the expression of programmed cell death ligand 1 (PD-L1), programmed cell death ligand 2 (PD-L2), and human leukocyte antigen G (HLA-G) molecules as well as the populations of CD4+ and CD8+ T lymphocytes, regulatory T cells (Tregs), and M2 macrophages (MM2). Several statistical tests, including multivariate analyses, were performed to examine how those immune cells and immunoinhibitory molecules impact the evolution and prognosis of pancreatic adenocarcinoma. RESULTS: CD8+ T lymphocytes and M2 macrophages predominated in the group operated on, and PD-L2 expression predominated in the unresectable group. PD-L2 was associated with T stage, lymph node metastasis, and clinical staging, while in survival analysis, PD-L2 and HLA-G were associated with a shorter survival. In the inoperable cases, Tregs cells, MM2, PD-L1, PD-L2, and HLA-G were positively correlated. CONCLUSIONS: PD-L2 and HLA-G expression correlated with worse survival in the cases studied. Tumor microenvironment was characterized by a tolerant and immunosuppressed pattern, mainly in unresectable lesions, where a broad positive influence was observed between immunoinhibitory cells and immune checkpoint proteins expressed by tumor cells.

Asunto(s)

Adenocarcinoma , Antígeno B7-H1 , Antígenos HLA-G , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Masculino , Femenino , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Persona de Mediana Edad , Anciano , Microambiente Tumoral/inmunología , Antígeno B7-H1/metabolismo , Antígenos HLA-G/metabolismo , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Pronóstico , Linfocitos T CD8-positivos/inmunología , Adulto , Linfocitos T Reguladores/inmunología , Anciano de 80 o más Años , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología

RESUMEN

PURPOSE: This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome. RESULTS: Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively. CONCLUSIONS: Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Proteínas de Punto de Control Inmunitario/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Linfocitos T Reguladores/efectos de los fármacos , Anciano , Albúminas/uso terapéutico , Linfocitos T CD4-Positivos/química , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD8-positivos/química , Linfocitos T CD8-positivos/efectos de los fármacos , Carcinoma Ductal Pancreático/inmunología , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Femenino , Fluorouracilo/uso terapéutico , Factores de Transcripción Forkhead , Receptor 2 Celular del Virus de la Hepatitis A/análisis , Humanos , Proteínas de Punto de Control Inmunitario/análisis , Irinotecán/uso terapéutico , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Oxaliplatino/uso terapéutico , Paclitaxel/uso terapéutico , Neoplasias Pancreáticas/inmunología , Proyectos Piloto , Receptor de Muerte Celular Programada 1/análisis , Receptor de Muerte Celular Programada 1/efectos de los fármacos , Supervivencia sin Progresión , Estudios Prospectivos , Linfocitos T Reguladores/química , Gemcitabina

RESUMEN

PURPOSE: Chemotherapy for advanced pancreatic cancer has limited efficacy due to the difficultly of treating established tumours and the evolution of tumour resistance. Chemotherapies for pancreatic cancer are typically studied for their cytotoxic properties rather than for their ability to increase the immunogenicity of pancreatic tumour cells. In this study Gemcitabine in combination with immune modulatory chemotherapies Oxaliplatin, zoledronic acid and pomalidomide was studied to determine how combination therapy alters the immunogenicity of pancreatic tumour cell lines and subsequent T-cell responses. METHODS: Pancreatic tumour cell lines were stimulated with the chemotherapeutic agents and markers of immune recognition were assessed. The effect of chemotherapeutic agents on DC function was measured using uptake of CFSE-stained PANC-1 cells, changes in markers of maturation and their ability to activate CD8+ T-cells. The effect of chemotherapeutic agents on T-cell priming prior to activation using anti-CD3 and anti-CD28 antibodies was determined by measuring IFN-γ expression and Annexin V staining using flow cytometry. RESULTS: These agents demonstrate both additive and inhibitory properties on a range of markers of immunogenicity. Gemcitabine was notable for its ability to induce the upregulation of human leukocyte antigen and checkpoints on pancreatic tumour cell lines whilst inhibiting T-cell activation. Pomalidomide demonstrated immune modulatory properties on dendritic cells and T-cells, even in the presence of gemcitabine. DISCUSSION: These data highlight the complex interactions of different agents in the modulation of tumour immunogenicity and immune cell activation and emphasise the complexity in rationally designing chemo immunogenic combinations for use with immunotherapy.

Asunto(s)

Antimetabolitos Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Desoxicitidina/análogos & derivados , Inmunomodulación/efectos de los fármacos , Neoplasias Pancreáticas/inmunología , Anexina A5/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Desoxicitidina/farmacología , Interacciones Farmacológicas/inmunología , Antígenos de Histocompatibilidad Clase I/efectos de los fármacos , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Inmunomodulación/inmunología , Interferón gamma/metabolismo , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Oxaliplatino/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Talidomida/análogos & derivados , Talidomida/farmacología , Ácido Zoledrónico/farmacología , Gemcitabina

RESUMEN

INTRODUCTION: Due to the primary role of PD-1 and LAG-3 in regulating the immune response in tumors, there is a need to develop therapies focused on the inhibition of PD-1 and LAG-3 in order to improve the immune response in patients with cancer. The authors of US2018326054 patent propose a method to eradicate cancer by using bispecific anti-PD-1/LAG-3 antibodies. AREAS COVERED: The US2018326054 patent describes anti-PD-1/LAG3 antibodies, pharmaceutical composition that contains it, and their application for cancer treatment, particularly pancreatic carcinoma. Proof concept and preclinical results show anti-PD-1/LAG-3 bispecific antibodies bind and are internalized by CD4 + T cells thereby increasing their effector functions (release of Granzyme B and INF-γ) in the presence of tumor cells, and completely suppress tumors in a murine model. EXPERT OPINION: Anti-PD-1/LAG-3 bispecific antibodies of the US2018326054 patent are new in a general concept, but treatment data is only shown for pancreatic carcinoma. The results to be obtained in future clinical trials of safety and efficacy could conclude whether these bispecific anti-PD-1/LAG-3 antibodies will be useful in a cancer treatment scheme.

Asunto(s)

Anticuerpos Biespecíficos/administración & dosificación , Antígenos CD/inmunología , Neoplasias/terapia , Receptor de Muerte Celular Programada 1/inmunología , Animales , Anticuerpos Biespecíficos/inmunología , Humanos , Inmunoterapia/métodos , Ratones , Neoplasias/inmunología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/terapia , Patentes como Asunto , Proteína del Gen 3 de Activación de Linfocitos

RESUMEN

BACKGROUND: Family with sequence similarity 83 members H (FAM83H) is one member of Family with sequence similarity 83 (FAM83) family, which possess oncogenic properties in several types of cancer. However, the potential function of FAM83H in pancreatic cancer (PC) still remain unknown. AIM: This study aims to explore the role of FAM83H during pancreatic carcinogenesis and the regulation of immune infiltration in PC. METHODS: In the current study, the clinical significance and potential biological of FAM83H were evaluated by bioinformatics analysis. Possible associations between FAM83H expression and tumor immunity were analyzed using ESTIMATE algorithm and single-sample gene set enrichment analysis (ssGSEA). RESULTS: FAM83H expression was significantly upregulated in tumor tissues, and positively associated with higher histologic grade, tumor recurrence, and worse prognosis. FAM83H overexpression is notably associated with KRAS activation. And functional enrichment analysis demonstrated that FAM83H may be involved in positive regulation of cell proliferation and migration, Ras protein signal transduction, regulation of cell-matrix adhesion, epithelial to mesenchymal transition (EMT), TGF-ß receptor signaling in EMT, and activated NOTCH transmits signal to the nucleus. ESTIMATE algorithm and ssGSEA demonstrated that FAM83H overexpression suppressed the infiltration and antitumor activity of tumor-infiltrating lymphocytes (TILs), especially for CD8+ T cells. Besides, FAM83H overexpression significantly correlated with low expression of TIL-related gene markers (e.g. CD8A, CD8B, CD2, CD3D, and CD3E). CONCLUSION: The study suggests that FAM83H overexpression predicts poor prognosis and correlates with less CD8+ T cells infiltration and Ras-PI3K-Akt-mTOR signaling pathway in PC.

Asunto(s)

Linfocitos T CD8-positivos , Neoplasias Pancreáticas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Algoritmos , Movimiento Celular , Femenino , Humanos , Estimación de Kaplan-Meier , Linfocitos Infiltrantes de Tumor , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Transducción de Señal , Regulación hacia Arriba

RESUMEN

Type 1 conventional dendritic cells (cDC1s) are typically thought to be dysregulated secondarily to invasive cancer. Here, we report that cDC1 dysfunction instead develops in the earliest stages of preinvasive pancreatic intraepithelial neoplasia (PanIN) in the KrasLSL-G12D/+ Trp53LSL-R172H/+ Pdx1-Cre-driven (KPC) mouse model of pancreatic cancer. cDC1 dysfunction is systemic and progressive, driven by increased apoptosis, and results in suboptimal up-regulation of T cell-polarizing cytokines during cDC1 maturation. The underlying mechanism is linked to elevated IL-6 concomitant with neoplasia. Neutralization of IL-6 in vivo ameliorates cDC1 apoptosis, rescuing cDC1 abundance in tumor-bearing mice. CD8+ T cell response to vaccination is impaired as a result of cDC1 dysregulation. Yet, combination therapy with CD40 agonist and Flt3 ligand restores cDC1 abundance to normal levels, decreases cDC1 apoptosis, and repairs cDC1 maturation to drive superior control of tumor outgrowth. Our study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation during pancreatic carcinogenesis and suggests therapeutically tractable strategies toward cDC1 repair.

Asunto(s)

Carcinogénesis/inmunología , Células Dendríticas/inmunología , Neoplasias Experimentales/inmunología , Neoplasias Pancreáticas/inmunología , Anciano , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Carcinogénesis/genética , Carcinogénesis/patología , Células Dendríticas/patología , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología

RESUMEN

PURPOSE: Pancreatic cancer (PC) is one of the most aggressive malignancies with no effective treatment if diagnosed in advanced stage. Systemic inflammation is a recognized characteristic of cancer progression, and we believe that the understanding of the influence of inflammatory parameters may contribute to therapeutic improvement in PC. Here, we validated the Eosinophil/Lymphocyte Ratio (ELR) together with the Neutrophil/Lymphocyte Ratio (NLR) and their components, as prognostic factors in PC patients treated with chemoradiation. METHODS: A total of 66 consecutive patients (p) diagnosed with PC stage I-III and treated with External Beam Radiotherapy + chemotherapy ± surgery (28p) in our institution from 2007 to 2018 were retrospectively evaluated. The impact of pre-treatment ELR ≥ 0.04, NLR ≥ 1.9, neutrophilia (≥ 7.0 × 10(9)/l), eosinophilia (≥ 0.5 × 10(9)/l) and lymphopenia (< 1.0 × 10(9)/l) on Overall Survival (OS) and Time-to-Progression (TTP) was evaluated both in the entire cohort and separately according to surgical status. RESULTS: Higher ELR was associated with longer OS and TTP, both in surgically treated and not operable patients. On univariate analysis, elevated ELR was associated with better OS (HR = 0.3, 95% IC 0.13-0.65, p = 0.003), contrarily to neutrophilia (HR = 2.7, 95% IC 1.2-6.5, p = 0.026) and age > 50 years (HR = 2.6, 95% IC 1.03-6.6, p = 0.044), while NLR, lymphopenia and Ca-19.9 were not significant. On multivariate regression, independent prognosticators for OS were: ELR, age and neutrophilia; while for TTP: ELR, neutrophilia, eosinophilia and lymphopenia. CONCLUSIONS: The host's immune response influences survival outcomes of PC patients and may be of interest for future research.

Asunto(s)

Adenocarcinoma/mortalidad , Eosinófilos/patología , Evasión Inmune/inmunología , Inflamación/mortalidad , Linfocitos/patología , Neutrófilos/patología , Neoplasias Pancreáticas/mortalidad , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Adenocarcinoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Terapia Combinada , Eosinófilos/inmunología , Femenino , Estudios de Seguimiento , Humanos , Inflamación/inmunología , Inflamación/patología , Inflamación/terapia , Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia

RESUMEN

BACKGROUND/AIM: The aim of the current study was to investigate the synergistic efficacy of Robo1 bichimeric antigen receptor-natural killer cell (BiCAR-NK) immunotherapy and 125I seed brachytherapy in an orthotopic pancreatic cancer mouse model. MATERIALS AND METHODS: The orthotopic pancreatic tumor model was established with human pancreatic cancer BxPC-3 cells expressing red fluorescent protein. The mice were treated with 125I seed implantation alone or the combination of 125I seeds with Robo1-specific CAR-NK cells. To assess tumor inhibition, in vivo fluorescence imaging was conducted. 7 Tesla magnetic resonance (7T-MR) scanning was applied to measure the changes in the metabolic profiles of tumor tissues. RESULTS: Tumor size was significantly reduced in the 125I and 125I +CAR-NK treated group compared to the untreated group (p<0.05). The 125I seed +CAR-NK treated group showed significantly higher tumor reduction than 125I seed treatment alone (p<0.05). T1 diffusion weighted imaging (T1DWI) sequence showed that the tumors of the 125I +BiCAR-NK treated group had a significantly higher grey scale value than the tumors from the untreated control and the group treated with 125I seed alone (p<0.05). CONCLUSION: Robo1 specific CAR-NK immunotherapy enhances efficacy of 125I seed brachytherapy in an orthotopic pancreatic cancer mouse model.

Asunto(s)

Braquiterapia/métodos , Inmunoterapia , Radioisótopos de Yodo/uso terapéutico , Células Asesinas Naturales/inmunología , Proteínas del Tejido Nervioso/inmunología , Neoplasias Pancreáticas/terapia , Receptores de Antígenos/inmunología , Receptores Inmunológicos/inmunología , Animales , Apoptosis , Proliferación Celular , Citotoxicidad Inmunológica/inmunología , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Roundabout

RESUMEN

BACKGROUND: Pancreatic adenocarcinoma has a high mortality rate. A prognostic tool is essential for a better risk stratification. The neutrophil/lymphocyte ratio and adaptations and the platelet/lymphocyte ratio seem promising for this purpose. AIM: Evaluate the prognostic value of neutrophil/lymphocyte ratio, derived neutrophil/lymphocyte ratio and platelet/lymphocyte ratio, analyze the ideal cutoff values and investigate their utility in predicting resectability. METHODS: Data were collected of patients with pancreatic adenocarcinoma in Hospital de Clínicas de Porto Alegre between 2003 and 2013. The studied ratios were determined by blood count collected at hospital admission and after two cycles of palliative chemotherapy. RESULTS: Basal neutrophil/lymphocyte ratio, derived neutrophil/lymphocyte ratio and platelet/lymphocyte ratio did not have prognostic impact in survival (p=0.394, p=0.152, p=0.177 respectively). In subgroup analysis of patients submitted to palliative chemotherapy, neutrophil/lymphocyte ratio, derived neutrophil/lymphocyte ratio and platelet/lymphocyte ratio determined after two cycles of chemotherapy were prognostic for overall survival (p=0.003, p=0.009, p=0.001 respectively). The ideal cutoff values found were 4,11 for neutrophil/lymphocyte ratio (sensitivity 83%, specificity 75%), 2,8 for derived neutrophil/lymphocyte ratio (sensitivity 87%, specificity 62,5%) and 362 for platelet/lymphocyte ratio (sensitivity 91%, specificity 62,5%), Neutrophil/lymphocyte ratio, derived neutrophil/lymphocyte ratio and platelet/lymphocyte ratio were not able to predict resectability (p=0.88; p=0.99; p=0.64 respectively). CONCLUSIONS: Neutrophil/lymphocyte ratio, derived neutrophil/lymphocyte ratio and platelet/lymphocyte ratio are useful as prognostic markers of overall survival in patients with pancreatic adenocarcinoma submitted to palliative chemotherapy. Its use as resectability predictor could not be demonstrated.

Asunto(s)

Adenocarcinoma/sangre , Adenocarcinoma/inmunología , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/inmunología , Adenocarcinoma/mortalidad , Femenino , Humanos , Inflamación/sangre , Recuento de Leucocitos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Neutrófilos , Neoplasias Pancreáticas/mortalidad , Recuento de Plaquetas , Pronóstico , Análisis de Supervivencia

RESUMEN

ABSTRACT Background: Pancreatic adenocarcinoma has a high mortality rate. A prognostic tool is essential for a better risk stratification. The neutrophil/lymphocyte ratio and adaptations and the platelet/lymphocyte ratio seem promising for this purpose. Aim: Evaluate the prognostic value of neutrophil/lymphocyte ratio, derived neutrophil/lymphocyte ratio and platelet/lymphocyte ratio, analyze the ideal cutoff values and investigate their utility in predicting resectability. Methods: Data were collected of patients with pancreatic adenocarcinoma in Hospital de Clínicas de Porto Alegre between 2003 and 2013. The studied ratios were determined by blood count collected at hospital admission and after two cycles of palliative chemotherapy. Results: Basal neutrophil/lymphocyte ratio, derived neutrophil/lymphocyte ratio and platelet/lymphocyte ratio did not have prognostic impact in survival (p=0.394, p=0.152, p=0.177 respectively). In subgroup analysis of patients submitted to palliative chemotherapy, neutrophil/lymphocyte ratio, derived neutrophil/lymphocyte ratio and platelet/lymphocyte ratio determined after two cycles of chemotherapy were prognostic for overall survival (p=0.003, p=0.009, p=0.001 respectively). The ideal cutoff values found were 4,11 for neutrophil/lymphocyte ratio (sensitivity 83%, specificity 75%), 2,8 for derived neutrophil/lymphocyte ratio (sensitivity 87%, specificity 62,5%) and 362 for platelet/lymphocyte ratio (sensitivity 91%, specificity 62,5%), Neutrophil/lymphocyte ratio, derived neutrophil/lymphocyte ratio and platelet/lymphocyte ratio were not able to predict resectability (p=0.88; p=0.99; p=0.64 respectively). Conclusions: Neutrophil/lymphocyte ratio, derived neutrophil/lymphocyte ratio and platelet/lymphocyte ratio are useful as prognostic markers of overall survival in patients with pancreatic adenocarcinoma submitted to palliative chemotherapy. Its use as resectability predictor could not be demonstrated.

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RESUMO Racional: O adenocarcinoma pancreático apresenta alta taxa de mortalidade. Uma ferramenta que possa predizer adequadamente o seu prognóstico é fundamental para melhor estratificação de risco. A razão neutrófilos/linfócitos e suas adaptações e a razão plaquetas/linfócitos tem se mostrado promissores para este fim. Objetivo: Avaliar o valor prognóstico das razões neutrófilos/linfócitos, neutrófilos/linfócitos derivada e plaquetas/linfócitos, analisar os pontos de corte mais adequados e investigar sua utilidade como fator preditivo de ressecabilidade. Métodos: Foram coletados dados de pacientes com adenocarcinoma pancreático atendidos no Hospital de Clínicas de Porto Alegre entre 2003 e 2013. As razões estudadas foram determinadas com base nos hemogramas coletados na internação e após dois ciclos de quimioterapia paliativa. Resultados: As razões neutrófilos/linfócitos basal, neutrófilos/linfócitos derivada basal e plaquetas/linfócitos basal não tiveram impacto prognóstico na sobrevida (p=0,394, p=0,152, p=0,177 respectivamente). No subgrupo submetido a quimioterapia paliativa, as razões neutrófilos/linfócitos, neutrófilos/linfócitos derivada e plaquetas/linfócitos após dois ciclos de tratamento mostraram-se fatores prognósticos para sobrevida global (p=0,003, p=0,009 e p=0,001 respectivamente). Os pontos de corte encontrados foram 4,11 para neutrófilos/linfócitos (sensibilidade 83% e especificidade 75%), 362 para plaquetas/linfócitos (sensibilidade 91% e especificidade 62,5%) e 2,8 para neutrófilos/linfócitos derivada (sensibilidade 87% e especificidade 62,5%). As razões neutrófilos/linfócitos, neutrófilos/linfócitos derivada e plaquetas/linfócitos não se mostraram estatisticamente significativas como preditores para ressecabilidade (p=0,88; p=0,99 e p=0,64 respectivamente). Conclusões: As razões neutrófilos/linfócitos, neutrófilos/linfócitos derivada e plaquetas/linfócitos são úteis como marcadores prognósticos de sobrevida global em pacientes com adenocarcinoma pancreático submetidos à quimioterapia paliativa. Seu uso como preditor de ressecabilidade não foi demonstrado.

Asunto(s)

Humanos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/sangre , Adenocarcinoma/inmunología , Adenocarcinoma/sangre , Neoplasias Pancreáticas/mortalidad , Recuento de Plaquetas , Pronóstico , Adenocarcinoma/mortalidad , Análisis de Supervivencia , Recuento de Linfocitos , Inflamación/sangre , Recuento de Leucocitos , Neutrófilos

RESUMEN

Historically, patients diagnosed with metastatic pancreatic cancer have faced a grim prognosis. The survival benefit seen with systemic chemotherapies and even combinations thereof have been disappointing. However, growing data suggest that the microenvironment of pancreatic cancer may be contributing to this poor prognosis. This microenvironment has a dense fibrotic stroma, and is hypoxic and highly immunosuppressive, all of which pose barriers to treatment. Newer strategies looking to disrupt the fibrotic stroma, target hypoxic areas, and improve local immune responses in the tumor microenvironment are currently undergoing clinical evaluation and seem to offer great promise. In addition to these therapies, preclinical work evaluating novel cytotoxic agents including nanoparticles has also been encouraging. While much research still needs to be done, these strategies offer new hope for patients with pancreatic cancer.

Asunto(s)

Carcinoma Ductal Pancreático/inmunología , Neoplasias Pancreáticas/inmunología , Microambiente Tumoral/inmunología , Carcinoma Ductal Pancreático/patología , Humanos , Neoplasias Pancreáticas/patología

RESUMEN

The initiation and progression of pancreatic ductal adenocarcinoma (PDA) occurs as a result of molecular alterations that typically result in fluctuations of transcription, protein expression, and ultimately dysregulated signaling pathways. For example, PDA is driven by key activating, gain-of-function mutations in proto-oncogenes (eg, K-Ras) along with loss of function of tumor suppressor genes (eg, p16, SMAD4). With the advent of whole-exome sequencing of PDA genomes, several key genetic alterations have been identified as drivers of PDA. While these findings have led to groundbreaking discoveries in the etiology of PDA, they have failed to provide feasible, targetable therapeutic approaches. Additionally, recent advances in PDA research have uncovered the role of the tumor microenvironment (the non-epithelial tumor cells) in PDA progression by promoting potent, acute changes in gene expression. Herein, this chapter is aimed at discussing the key genetic and non-genetic mechanisms responsible for PDA initiation and progression. Thus based on these mechanisms, we will put forth investigated and novel therapeutic targets in PDA.

Asunto(s)

Carcinoma Ductal Pancreático/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/metabolismo , Humanos , Inmunomodulación , Terapia Molecular Dirigida , Mutación , Oncogenes , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/metabolismo

RESUMEN

Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to late detection and resistance to conventional therapies. Published studies show that the PDA tumor microenvironment is predominantly infiltrated with immune suppressive cells and signals that if altered, would allow effective immunotherapy. However, single-agent checkpoint inhibitors including agents that alter immune suppressive signals in other human cancers such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand PD-L1, have failed to demonstrate objective responses when given as single agents to PDA patients. We recently reported that inhibition of the CTLA-4 pathway when given together with a T cell inducing vaccine gives objective responses in metastatic PDA patients. In this study, we evaluated blockade of the PD-1/PD-L1 pathway. We found that PD-L1 is weakly expressed at a low frequency in untreated human and murine PDAs but treatment with a granulocyte macrophage colony-stimulating factor secreting PDA vaccine (GVAX) significantly upregulates PD-L1 membranous expression after treatment of tumor-bearing mice. In addition, combination therapy with vaccine and PD-1 antibody blockade improved murine survival compared with PD-1 antibody monotherapy or GVAX therapy alone. Furthermore, PD-1 blockade increased effector CD8 T lymphocytes and tumor-specific interferon-γ production of CD8 T cells in the tumor microenvironment. Immunosuppressive pathways, including regulatory T cells and CTLA-4 expression on T cells were overcome by the addition of vaccine and low-dose cyclophosphamide to PD-1 blockade. Collectively, our study supports combining PD-1 or PD-L1 antibody therapy with a T cell inducing agent for PDA treatment.

Asunto(s)

Antígeno B7-H1/antagonistas & inhibidores , Vacunas contra el Cáncer/inmunología , Carcinoma Ductal Pancreático/inmunología , Neoplasias Pancreáticas/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Animales , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Inmunoterapia/métodos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Endogámicos C57BL

RESUMEN

Off-target toxicity due to the expression of target antigens in normal tissue represents a major obstacle to the use of chimeric antigen receptor (CAR)-engineered T cells for treatment of solid malignancies. To circumvent this issue, we established a clinical platform for engineering T cells with transient CAR expression by using in vitro transcribed mRNA encoding a CAR that includes both the CD3-ζ and 4-1BB co-stimulatory domains. We present two case reports from ongoing trials indicating that adoptive transfer of mRNA CAR T cells that target mesothelin (CARTmeso cells) is feasible and safe without overt evidence of off-tumor on-target toxicity against normal tissues. CARTmeso cells persisted transiently within the peripheral blood after intravenous administration and migrated to primary and metastatic tumor sites. Clinical and laboratory evidence of antitumor activity was demonstrated in both patients and the CARTmeso cells elicited an antitumor immune response revealed by the development of novel anti-self antibodies. These data demonstrate the potential of utilizing mRNA engineered T cells to evaluate, in a controlled manner, potential off-tumor on-target toxicities and show that short-lived CAR T cells can induce epitope-spreading and mediate antitumor activity in patients with advanced cancer. Thus, these findings support the development of mRNA CAR-based strategies for carcinoma and other solid tumors.

Asunto(s)

Proteínas Ligadas a GPI/inmunología , Inmunoterapia Adoptiva/métodos , Neoplasias Pulmonares/terapia , Mesotelioma/terapia , Neoplasias Pancreáticas/terapia , Neoplasias Pleurales/terapia , Receptores de Antígenos de Linfocitos T/genética , Anciano , Anciano de 80 o más Años , Quimerismo , Electroporación/métodos , Estudios de Factibilidad , Ingeniería Genética/métodos , Humanos , Inmunoterapia Adoptiva/efectos adversos , Neoplasias Pulmonares/inmunología , Masculino , Mesotelina , Mesotelioma/inmunología , Mesotelioma Maligno , Neoplasias Pancreáticas/inmunología , Neoplasias Pleurales/inmunología , ARN Mensajero/genética , Receptores de Antígenos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/inmunología

RESUMEN

PURPOSE: Regulatory T cells (Tregs) play a role in the immunosuppressive state in pancreatic cancer patients. We aimed to evaluate the changes of immune cells population including Tregs caused by gemcitabine (GEM)-based chemotherapy. METHODS: Fifty-three patients with pancreatic cancer were enrolled in this study, of which 32 received GEM- based chemotherapy. Blood samples were collected before and at least 2 weeks after the last dose of chemotherapy. The peripheral blood mononuclear cells (PBMCs) were subjected to flow cytometry analysis after labeling with anti-CD4, anti-CD25, and anti-Foxp3 antibodies. Other lymphocytes and NK cell markers were also measured. The proliferative capacity of PBMCs stimulated with anti-CD3 was analyzed using H(3) thymidine. RESULTS: The percentage and number of Tregs were significantly decreased after chemotherapy (p = 0.032, p = 0.003, respectively). The other immune cells and the proliferative capacity did not change. CONCLUSION: This study showed that GEM-based chemotherapy produced an immunomodulatory effect via the depletion of Tregs.

Asunto(s)

Antimetabolitos Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Desoxicitidina/uso terapéutico , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/sangre , Gemcitabina

RESUMEN

Resumo: O pâncreas pode ser acometido por neoplasias de origem epitelial, de células de ilhotas pancreáticas, tumores exócrinos, linfomas metástases. O objetivo deste trabalho é apresentar as principais características deste grupo de tumores, com intúito de diferenciá-los.

Asunto(s)

Humanos , Neoplasias Pancreáticas , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas

RESUMEN

Cellular immune-response during pancreatic carcinogenesis induced by N-nitroso-bis(2-hydroxy-propyl)amine in Syrian Golden hamsters was studied using a mouse antiserum to hamster T-lymphocytes in indirect immunofluorescence. The chronology of lesions in this model is, acinar cell atypia, cystadenoma, ductal hyperplasia and adenocarcinoma. Lymphocyte infiltration began before microscopic lesions. Starting as an interstitial and interlobular migration, this earliest population was composed of various kind of mononuclear cells including T-cells. As pancreatic lesions proceeded, an abundant lymphocyte supply through newly formed capillaries (angiogenesis), gave rise to inter- and intralobular nodules composed almost exclusively of T-cells. Migrating from nodules, T-cells invaded and readily destroyed the exocrine tissue. Formation of hyperplasic ducts and of adenocarcinoma was accompanied by considerable accretion of the basal membrane (fibrosis). T-cells were located outside and around this basal membrane so that they never invaded the ductal epithelium. Our results suggest there is an effective immunosurveillance in the early stages of transformation that becomes ineffective at later stages as a consequence of T-cells' inability to pass through the basal membrane barrier surrounding the ductal epithelium in preneoplasic lesions (ductal hyperplasia) and in adenocarcinoma. Extending our observations to human pancreatic cancer could provide a new insight in cellular immunosurveillance and, as a consequence might, help cellular immunotherapeutic approaches for this almost fatal disease.

Asunto(s)

Neoplasias Pancreáticas/inmunología , Lesiones Precancerosas/inmunología , Linfocitos T/inmunología , Animales , Cricetinae , Masculino , Mesocricetus , Nitrosaminas/toxicidad , Páncreas/patología , Neoplasias Pancreáticas/inducido químicamente , Neoplasias Pancreáticas/patología , Lesiones Precancerosas/inducido químicamente , Lesiones Precancerosas/patología

RESUMEN

Apresenta-se um novo marcador tumoral, o CA 19.9. Os estudos envolveram inicialmente 29 pacientes portadores de adenocarcinoma gastrintestinal e de mama aonde näo se demonstrou qualquer tipo de especificidade, sendo os resultados obtidos no entanto superiores aos valores normais. Onze pacientes com câncer de pâncreas apresentaram os valores mais elevados do estudo, ao contrário de pacientes com doenças que estäo no diagnóstico diferencial de afecçöes pancreáticas. Um estudo comparativo entre o CEA e o CA 19.9 neste grupo de pacientes mostrou ser o CA 19.9 superior ao CEA na monitorizaçäo do câncer de pâncreas. Dos estudos pode-se ver que o CEA 19.9 se mostrou altamente específico para o diagnóstico de adenocarcinoma de pâncreas e altamente sensível para o diagnóstico de adenocarcinoma. Provou ser também, no carcinoma de pâncreas, um melhor marcador que o CEA

Asunto(s)

Humanos , Neoplasias Pancreáticas/inmunología , Adenocarcinoma/inmunología , Antígeno Carcinoembrionario/inmunología , Antígenos de Neoplasias/inmunología

Asunto(s)

Adenocarcinoma/inmunología , Antígenos de Neoplasias/inmunología , Antígeno Carcinoembrionario/inmunología , Neoplasias Pancreáticas/inmunología , Antígenos de Carbohidratos Asociados a Tumores , Humanos