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1.
Mol Cancer ; 23(1): 37, 2024 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-38374062

RESUMEN

Soft tissue sarcomas (STS) are diverse mesenchymal tumors with few therapeutic options in advanced stages. Trabectedin has global approval for treating STS patients resistant to anthracycline-based regimens. Recent pre-clinical data suggest that trabectedin's antitumor activity extends beyond tumor cells to influencing the tumor microenvironment (TME), especially affecting tumor-associated macrophages and their pro-tumoral functions. We present the phase I/II results evaluating a combination of metronomic trabectedin and low-dose cyclophosphamide on the TME in patients with advanced sarcomas. 50 patients participated: 20 in phase I and 30 in phase II. Changes in the TME were assessed in 28 patients using sequential tumor samples at baseline and day two of the cycle. Treatment notably decreased CD68 + CD163 + macrophages in biopsies from tumor lesions compared to pre-treatment samples in 9 of the 28 patients after 4 weeks. Baseline CD8 + T cell presence increased in 11 of these patients. In summary, up to 57% of patients exhibited a positive immunological response marked by reduced M2 macrophages or increased CD8 + T cells post-treatment. This positive shift in the TME correlated with improved clinical benefit and progression-free survival. This study offers the first prospective evidence of trabectedin's immunological effect in advanced STS patients, highlighting a relationship between TME modulation and patient outcomes.This study was registered with ClinicalTrial.gov, number NCT02406781.


Asunto(s)
Antineoplásicos Alquilantes , Sarcoma , Humanos , Trabectedina/uso terapéutico , Estudios Prospectivos , Antineoplásicos Alquilantes/uso terapéutico , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Ciclofosfamida/uso terapéutico , Dioxoles , Microambiente Tumoral
2.
Cell Rep Med ; 4(11): 101287, 2023 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-37967556

RESUMEN

The efficacy of immune checkpoint inhibitors varies in clear-cell renal cell carcinoma (ccRCC), with notable primary resistance among patients. Here, we integrate epigenetic (DNA methylation) and transcriptome data to identify a ccRCC subtype characterized by cancer-specific promoter hypermethylation and epigenetic silencing of Polycomb targets. We develop and validate an index of methylation-based epigenetic silencing (iMES) that predicts primary resistance to immune checkpoint inhibition (ICI) in the BIONIKK trial. High iMES is associated with VEGF pathway silencing, endothelial cell depletion, immune activation/suppression, EZH2 activation, BAP1/SETD2 deficiency, and resistance to ICI. Combination therapy with hypomethylating agents or tyrosine kinase inhibitors may benefit patients with high iMES. Intriguingly, tumors with low iMES exhibit increased endothelial cells and improved ICI response, suggesting the importance of angiogenesis in ICI treatment. We also develop a transcriptome-based analogous system for extended applicability of iMES. Our study underscores the interplay between epigenetic alterations and tumor microenvironment in determining immunotherapy response.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Metilación de ADN/genética , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Microambiente Tumoral/genética , Células Endoteliales/metabolismo , Inmunoterapia
3.
Cancer Res ; 83(17): 2952-2969, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37335139

RESUMEN

Immune checkpoint inhibitors (ICI) represent the cornerstone for the treatment of patients with metastatic clear cell renal cell carcinoma (ccRCC). Despite a favorable response for a subset of patients, others experience primary progressive disease, highlighting the need to precisely understand the plasticity of cancer cells and their cross-talk with the microenvironment to better predict therapeutic response and personalize treatment. Single-cell RNA sequencing of ccRCC at different disease stages and normal adjacent tissue (NAT) from patients identified 46 cell populations, including 5 tumor subpopulations, characterized by distinct transcriptional signatures representing an epithelial-to-mesenchymal transition gradient and a novel inflamed state. Deconvolution of the tumor and microenvironment signatures in public data sets and data from the BIONIKK clinical trial (NCT02960906) revealed a strong correlation between mesenchymal-like ccRCC cells and myofibroblastic cancer-associated fibroblasts (myCAF), which are both enriched in metastases and correlate with poor patient survival. Spatial transcriptomics and multiplex immune staining uncovered the spatial proximity of mesenchymal-like ccRCC cells and myCAFs at the tumor-NAT interface. Moreover, enrichment in myCAFs was associated with primary resistance to ICI therapy in the BIONIKK clinical trial. These data highlight the epithelial-mesenchymal plasticity of ccRCC cancer cells and their relationship with myCAFs, a critical component of the microenvironment associated with poor outcome and ICI resistance. SIGNIFICANCE: Single-cell and spatial transcriptomics reveal the proximity of mesenchymal tumor cells to myofibroblastic cancer-associated fibroblasts and their association with disease outcome and immune checkpoint inhibitor response in clear cell renal cell carcinoma.


Asunto(s)
Fibroblastos Asociados al Cáncer , Carcinoma de Células Renales , Neoplasias Renales , Humanos , Fibroblastos Asociados al Cáncer/patología , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Perfilación de la Expresión Génica , Inmunoterapia , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Pronóstico , Microambiente Tumoral , Ensayos Clínicos como Asunto
4.
Nat Rev Clin Oncol ; 19(7): 441-457, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35365796

RESUMEN

B cells are a major component of the tumour microenvironment, where they are predominantly associated with tertiary lymphoid structures (TLS). In germinal centres within mature TLS, B cell clones are selectively activated and amplified, and undergo antibody class switching and somatic hypermutation. Subsequently, these B cell clones differentiate into plasma cells that can produce IgG or IgA antibodies targeting tumour-associated antigens. In tumours without mature TLS, B cells are either scarce or differentiate into regulatory cells that produce immunosuppressive cytokines. Indeed, different tumours vary considerably in their TLS and B cell content. Notably, tumours with mature TLS, a high density of B cells and plasma cells, as well as the presence of antibodies to tumour-associated antigens are typically associated with favourable clinical outcomes and responses to immunotherapy compared with those lacking these characteristics. However, polyclonal B cell activation can also result in the formation of immune complexes that trigger the production of pro-inflammatory cytokines by macrophages and neutrophils. In complement-rich tumours, IgG antibodies can also activate the complement cascade, resulting in the production of anaphylatoxins that sustain tumour-promoting inflammation and angiogenesis. Herein, we review the phenotypic heterogeneity of intratumoural B cells and the importance of TLS in their generation as well as the potential of B cells and TLS as prognostic and predictive biomarkers. We also discuss novel therapeutic approaches that are being explored with the aim of increasing mature TLS formation, B cell differentiation and anti-tumour antibody production within tumours.


Asunto(s)
Neoplasias , Estructuras Linfoides Terciarias , Antígenos de Neoplasias , Citocinas , Humanos , Inmunoglobulina G , Neoplasias/patología , Estructuras Linfoides Terciarias/patología , Microambiente Tumoral
5.
Lancet Oncol ; 23(5): 612-624, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35390339

RESUMEN

BACKGROUND: We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab-ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups. METHODS: This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab-ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab-ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab-ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment. FINDINGS: Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab-ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6-18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16-45) of 42 patients with nivolumab and 16 (39%; 24-55) of 41 patients with nivolumab-ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25-1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20-70) of 16 patients with nivolumab and nine (50% 26-74) of 18 patients with nivolumab-ipilimumab (OR 0·78 [95% CI 0·20-3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33-67) of 36 patients with a VEGFR-TKI and 19 (51%; 34-68) of 37 patients with nivolumab-ipilimumab (OR 0·95 [95% CI 0·38-2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1-72) of five patients who received nivolumab-ipilimumab. The most common treatment-related grade 3-4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab-ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab-ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab-ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib. INTERPRETATION: We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma. FUNDING: Bristol Myers Squibb, ARTIC.


Asunto(s)
Carcinoma de Células Renales , Nivolumab , Inhibidores de la Angiogénesis/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores , Carcinoma de Células Renales/tratamiento farmacológico , Femenino , Humanos , Ipilimumab , Lipasa , Masculino , Estadificación de Neoplasias , Nivolumab/efectos adversos , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Sunitinib , Microambiente Tumoral
6.
J Exp Med ; 218(1)2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33601413

RESUMEN

Whereas T cells have been considered the major immune cells of the tumor microenvironment able to induce tumor regression and control cancer clinical outcome, a burst of recent publications pointed to the fact that B cells may also play a prominent role. Activated in germinal centers of tertiary lymphoid structures, B cells can directly present tumor-associated antigens to T cells or produce antibodies that increase antigen presentation to T cells or kill tumor cells, resulting in a beneficial clinical impact. Immune complexes can also increase inflammation, angiogenesis, and immunosuppression via macrophage and complement activation, resulting in deleterious impact.


Asunto(s)
Antígenos de Neoplasias/inmunología , Linfocitos B/inmunología , Neoplasias/inmunología , Neovascularización Patológica/inmunología , Microambiente Tumoral/inmunología , Animales , Linfocitos B/patología , Activación de Complemento , Humanos , Inflamación/inmunología , Inflamación/patología , Macrófagos/patología , Neoplasias/irrigación sanguínea , Neoplasias/patología , Neovascularización Patológica/patología , Linfocitos T/inmunología , Linfocitos T/patología
7.
Semin Immunol ; 48: 101406, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-33248905

RESUMEN

Tumors progression is under the control of a heterogeneous microenvironment composed of immune cells, fibroblasts, blood and lymphatic vessels, in which T cells have been demonstrated to be major actors, through their cytotoxic and cytokine producing effector functions and their long term memory that protects against metastasis. In this scenario, lessons from mouse models taught that B cells exert a protumoral role, via macrophage-dependent activation of inflammation. However, it became progressively evident from studies in patients with human cancers that the anti-tumor responses can be generated and controlled in tertiary lymphoid structures (TLS) that concentrate most of the intratumoral B cells and where B cells can differentiate into plasma cells and memory cells. Furthermore, recent studies demonstrated that the presence in tumors of B cells and TLS are associated with favorable outcome in patients treated by immunotherapy, unraveling TLS as a new predictive marker of anti-tumor response human cancers. This review encompasses the characteristics and functions of TLS and of B cells in human tumors, their prognostic and theranostic impact and summarizes the mouse models used to induce TLS neogenesis in tumors.


Asunto(s)
Linfocitos B/inmunología , Biomarcadores de Tumor/inmunología , Inmunoterapia/métodos , Neoplasias/terapia , Linfocitos T/inmunología , Estructuras Linfoides Terciarias/inmunología , Animales , Biomarcadores Farmacológicos , Humanos , Inmunomodulación , Neoplasias/inmunología , Microambiente Tumoral
8.
Semin Immunol ; 48: 101410, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-33011065

RESUMEN

Among all immune cells, dendritic cells (DC) are the most potent APCs in the immune system and are central players of the adaptive immune response. There are phenotypically and functionally distinct DC populations derived from blood and lymphoid organ including plasmacytoid DC (pDC), conventional DC (cDC1 and cDC2) and monocyte-derived DC (moDC). The interaction between these different DCs and tumors is a dynamic process where DC-mediated cross-priming of tumor specific T cells is critical in initiating and sustaining anti-tumor immunity. Their presence within the tumor tends to induce T cell responses and to reduce cancer progression and is associated with improved patient survival. This review will focus on the distinct tumor-associated DCs (TADC) subsets in the tumor microenvironment (TME), their roles in tumor immunology and their prognostic and/or predictive impact in human cancers. The development of therapeutic immunity strategies targeting TADC is promising to enhance their immune-stimulatory capacity in cancers and improve the efficacy of current immunotherapies including immune checkpoint inhibitor (ICI) blockade and DC-based therapies.


Asunto(s)
Células Dendríticas/inmunología , Inmunoterapia Adoptiva/métodos , Linfocitos T/inmunología , Animales , Presentación de Antígeno , Antígenos de Neoplasias/metabolismo , Humanos , Activación de Linfocitos , Neoplasias/diagnóstico , Neoplasias/inmunología , Neoplasias/terapia , Microambiente Tumoral
9.
Genome Med ; 12(1): 86, 2020 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-33023656

RESUMEN

Quantifying tissue-infiltrating immune and stromal cells provides clinically relevant information for various diseases. While numerous methods can quantify immune or stromal cells in human tissue samples from transcriptomic data, few are available for mouse studies. We introduce murine Microenvironment Cell Population counter (mMCP-counter), a method based on highly specific transcriptomic markers that accurately quantify 16 immune and stromal murine cell populations. We validated mMCP-counter with flow cytometry data and showed that mMCP-counter outperforms existing methods. We showed that mMCP-counter scores are predictive of response to immune checkpoint blockade in cancer mouse models and identify early immune impacts of Alzheimer's disease.


Asunto(s)
Microambiente Celular/genética , Leucocitos/metabolismo , Células del Estroma/metabolismo , Transcriptoma , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Biomarcadores , Microambiente Celular/efectos de los fármacos , Microambiente Celular/inmunología , Biología Computacional/métodos , Bases de Datos Genéticas , Femenino , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Inhibidores de Puntos de Control Inmunológico/farmacología , Proteínas de Punto de Control Inmunitario/metabolismo , Leucocitos/efectos de los fármacos , Leucocitos/inmunología , Ratones , Curva ROC , Análisis de la Célula Individual , Células del Estroma/efectos de los fármacos , Células del Estroma/patología
10.
Bull Cancer ; 107(5S): S24-S34, 2020 Jun.
Artículo en Francés | MEDLINE | ID: mdl-32620204

RESUMEN

The standard of care for metastatic clear cell renal cell carcinoma (mccRCC) has changed dramatically over the past decades thanks to the increasing number of treatments: anti-VEGFR tyrosine kinase inhibitors (TKI), mTOR inhibitors and immune checkpoint inhibitors (ICI): anti PD(L)-1 used as monotherapy or in combination with anti CTLA-4 or anti angiogenic therapies. In the face of rising therapeutic options, the question of the therapeutic sequences arises: which treatment for which patient? Actually, there is a lack of predictive biomarkers. A greater understanding of the cancer biology and its interaction with the microenvironment has allowed the development of genomic signatures which could perhaps be used as predictive biomarker. This review will give an insight on some robust genomic signatures assessed in mccRCC and will have a closer look at BIONIKK phase II trial, which is the first trial to adapt treatments according to the molecular characteristics of the tumor in the context of mccRCC.


Asunto(s)
Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Carcinoma de Células Renales/secundario , Toma de Decisiones Clínicas , Humanos , Neoplasias Renales/patología , Guías de Práctica Clínica como Asunto
11.
Bull Cancer ; 107(5S): eS22-eS27, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32620212

RESUMEN

BACKGROUND: The nivolumab-ipilimumab combination provides an overall response rate of 42% in first-line metastatic treatment of clear cell renal carcinoma (mccRCC). To date, there is no robust predictive biomarker of response to immune checkpoint inhibitor (ICI). In addition, severe autoimmune disorders occur more frequently with ICI combination than with ICI alone. The objective of this study is to compare the efficacy of ICI alone or in combination in patients according to tumor molecular characteristics. METHODS: Using a 35-gene expression mRNA signature, patients were divided into 4 molecular groups (1 to 4). Patients in groups 1 and 4 were randomized to receive nivolumab alone (arms 1A and 4A) or nivolumab plus ipilimumab for 4 injections followed by nivolumab alone (arms 1B and 4B). Patients in groups 2 and 3 were randomized to receive nivolumab plus ipilimumab followed by nivolumab alone (arms 2B and 3B) or a tyrosine kinase inhibitor (sunitinib or pazopanib at the investigator's choice (arms 2C and 3C)). The main objective is the overall response rate by treatment and molecular group. DISCUSSION: BIONIKK is the first trial in mccRCC to study the personalization of treatment with ICI or TKI according to tumor molecular characteristics in mccRCC. This trial is the most appropriate to prospectively identify biomarkers of response to nivolumab used alone or in combination or TKI monotherapy in patients with mccRCC. NCT02960906.


Asunto(s)
Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ensayos Clínicos Fase II como Asunto/métodos , Ipilimumab/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Nivolumab/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Sulfonamidas/administración & dosificación , Sunitinib/administración & dosificación , Biomarcadores de Tumor , Quimioterapia Combinada , Humanos , Indazoles , Neoplasias Renales/patología , Metástasis de la Neoplasia , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores
12.
Nature ; 577(7791): 556-560, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31942077

RESUMEN

Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes1,2. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely3,4. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.


Asunto(s)
Linfocitos B/inmunología , Inmunoterapia , Sarcoma/tratamiento farmacológico , Sarcoma/inmunología , Estructuras Linfoides Terciarias/inmunología , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Estudios de Cohortes , Células Dendríticas Foliculares/inmunología , Humanos , Mutación , Fenotipo , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Reproducibilidad de los Resultados , Sarcoma/clasificación , Sarcoma/patología , Tasa de Supervivencia , Microambiente Tumoral
13.
Cancer Immunol Res ; 7(7): 1091-1105, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31164356

RESUMEN

Clear-cell renal cell carcinoma (ccRCC) possesses an unmet medical need, particularly at the metastatic stage, when surgery is ineffective. Complement is a key factor in tissue inflammation, favoring cancer progression through the production of complement component 5a (C5a). However, the activation pathways that generate C5a in tumors remain obscure. By data mining, we identified ccRCC as a cancer type expressing concomitantly high expression of the components that are part of the classical complement pathway. To understand how the complement cascade is activated in ccRCC and impacts patients' clinical outcome, primary tumors from three patient cohorts (n = 106, 154, and 43), ccRCC cell lines, and tumor models in complement-deficient mice were used. High densities of cells producing classical complement pathway components C1q and C4 and the presence of C4 activation fragment deposits in primary tumors correlated with poor prognosis. The in situ orchestrated production of C1q by tumor-associated macrophages (TAM) and C1r, C1s, C4, and C3 by tumor cells associated with IgG deposits, led to C1 complex assembly, and complement activation. Accordingly, mice deficient in C1q, C4, or C3 displayed decreased tumor growth. However, the ccRCC tumors infiltrated with high densities of C1q-producing TAMs exhibited an immunosuppressed microenvironment, characterized by high expression of immune checkpoints (i.e., PD-1, Lag-3, PD-L1, and PD-L2). Our data have identified the classical complement pathway as a key inflammatory mechanism activated by the cooperation between tumor cells and TAMs, favoring cancer progression, and highlight potential therapeutic targets to restore an efficient immune reaction to cancer.


Asunto(s)
Carcinoma de Células Renales/patología , Complemento C1q/inmunología , Complemento C3/inmunología , Complemento C4/inmunología , Neoplasias Renales/patología , Macrófagos/inmunología , Microambiente Tumoral/inmunología , Animales , Apoptosis , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/metabolismo , Proliferación Celular , Activación de Complemento , Complemento C1q/metabolismo , Complemento C3/metabolismo , Complemento C4/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Factores Inmunológicos/metabolismo , Neoplasias Renales/inmunología , Neoplasias Renales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Tasa de Supervivencia , Células Tumorales Cultivadas
14.
Surg Infect (Larchmt) ; 20(3): 219-224, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30657423

RESUMEN

AIM: To discuss the significance and applied value in the rapid identification and drug susceptibility test for blood stream infection (BSI) using matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) combined with flow cytometry (FCM). METHODS: The bacteria were separated from the positive blood culture bottle using the separation gel-adsorption method system, and then applying MALDI-TOF MS combined with FCM to identify pathogen and drug susceptibility test quickly. RESULTS: The efficiency of the separation gel-adsorption method for gram-negative bacterium, gram-positive bacteria, and fungi is 71%, 74%, and 88%, respectively. The results of identifying pathogens using MALDI-TOFMS are in agreement with results obtained using VITEK®2 (bioMérieux, Marcy l'Etoile, France); both methods can identify 90% of bacteria to species. For fungi, MALDI-TOF MS can identify 75% fungi to species, which is superior to VITEK2, which identifies 60% fungi to species. The results of drug susceptibility test using FCM are almost identical to VITEK2; additionally, the addition of fluorescein diacetate can identify the heterogenic drug-resistant strains. CONCLUSIONS: We can quickly identify pathogen and drug-susceptibility test based on MALDI-TOF MS combined with FCM, which is consistent with traditional methods and can shorten the report time from 36-72 hour to 3 hours. More importantly, these methods are of great significance and clinical importance for the rapid identification of BSI.


Asunto(s)
Bacterias/aislamiento & purificación , Farmacorresistencia Bacteriana , Citometría de Flujo/métodos , Hongos/aislamiento & purificación , Técnicas Microbiológicas/métodos , Sepsis/diagnóstico , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Bacterias/clasificación , Bacterias/efectos de los fármacos , Hongos/clasificación , Hongos/efectos de los fármacos , Humanos , Sepsis/microbiología , Factores de Tiempo
15.
Front Oncol ; 8: 390, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30319963

RESUMEN

Tumors are formed by aggregates of cells of various origins including malignant, stromal and immune cells. The number of therapies targeting the microenvironment is increasing as the tumor microenvironment is more and more recognized as playing an essential role in tumor control. In the era of precision medicine, it is essential to precisely estimate the composition, organization and functionality of the individual patient tumor microenvironment and to find ways to therapeutically modulate it. To quantify the cell populations present in the tumor microenvironment, many tools are now available and the most recent approaches will be reviewed herein. We provide an overview of experimental and computational methodologies used to quantify tumor-associated cellular populations, including immunohistochemistry, flow and mass cytometry, bulk and single-cell transcriptomic approaches. We illustrate their respective contribution to characterize the microenvironment. We also discuss how these methods allow to guide therapeutic choices, in relation to the predictive value of some characteristics of the microenvironment.

16.
Int J Cancer ; 139(6): 1358-71, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27130719

RESUMEN

Enhancing anti-tumor immunity and preventing tumor escape are efficient strategies to increase the efficacy of therapeutic cancer vaccines. However, the treatment of advanced tumors remains difficult, mainly due to the immunosuppressive tumor microenvironment. Regulatory T cells and myeloid-derived suppressor cells have been extensively studied, and their role in suppressing tumor immunity is now well established. In contrast, the role of B lymphocytes in tumor immunity remains unclear because B cells can promote tumor immunity or display regulatory functions to control excessive inflammation, mainly through IL-10 secretion. Here, in a mouse model of HPV-related cancer, we demonstrate that B cells accumulated in the draining lymph node of tumor-bearing mice, due to a prolonged survival, and showed a decreased expression of MHC class II and CD86 molecules and an increased expression of Ly6A/E, PD-L1 and CD39, suggesting potential immunoregulatory properties. However, B cells from tumor-bearing mice did not show an increased ability to secrete IL-10 and a deficiency in IL-10 production did not impair tumor growth. In contrast, in B cell-deficient µMT mice, tumor rejection occurred due to a strong T cell-dependent anti-tumor response. Genetic analysis based on single nucleotide polymorphisms identified genetic variants associated with tumor rejection in µMT mice, which could potentially affect reactive oxygen species production and NK cell activity. Our results demonstrate that B cells play a detrimental role in anti-tumor immunity and suggest that targeting B cells could enhance the anti-tumor response and improve the efficacy of therapeutic cancer vaccines.


Asunto(s)
Linfocitos B/inmunología , Linfocitos B/metabolismo , Infecciones por Papillomavirus/complicaciones , Neoplasias del Cuello Uterino/etiología , Neoplasias del Cuello Uterino/metabolismo , Animales , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Subgrupos de Linfocitos B/patología , Linfocitos B/patología , Movimiento Celular/inmunología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Estudio de Asociación del Genoma Completo , Interleucina-10/biosíntesis , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Activación de Linfocitos , Ratones , Papillomaviridae , Infecciones por Papillomavirus/virología , Fenotipo , Polimorfismo de Nucleótido Simple , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Receptor Toll-Like 9/metabolismo , Neoplasias del Cuello Uterino/patología
17.
Chin Med J (Engl) ; 128(11): 1455-9, 2015 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-26021500

RESUMEN

BACKGROUND: Gastric stromal tumors arising from the muscularis propria are located in deeper layers. Endoscopic resection may be contraindicated due to the possibility of perforation. These tumors are therefore usually removed by surgical or laparoscopic procedures. This study evaluated the curative effects, safety and feasibility of endoscopic full-thickness resection (EFR) of gastric stromal tumors originating from the muscularis propria. METHODS: This study enrolled 92 patients with gastric stromal tumors >2.5 cm originating from the muscularis propria. Fifty patients underwent EFR, and 42 underwent laparoscopic intragastric surgery. Operation time, complete resection rate, length of hospital stay, incidence of complications, and recurrence rates were compared in these two groups. RESULTS: EFR resulted in complete resection of all 50 gastric stromal tumors, with a mean procedure time of 85 ± 20 min, a mean hospitalization time of 7.0 ± 1.5 days and no complications. Laparoscopic intragastric surgery also resulted in a 100% complete resection rate, with a mean operation time of 88 ± 12 min and a mean hospitalization period of 7.5 ± 1.6 days. The two groups did not differ significantly in operation time, complete resection rates, hospital stay or incidence of complications (P > 0.05). No patient in either group experienced tumor recurrence. CONCLUSIONS: EFR technique is effective and safe for the resection of gastric stromal tumors arising from the muscularis propria.


Asunto(s)
Laparoscopía/métodos , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Adulto , Femenino , Mucosa Gástrica/patología , Mucosa Gástrica/cirugía , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento
18.
Int J Clin Exp Med ; 8(11): 21746-54, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26885137

RESUMEN

PURPOSE: We aim to report a genetic testing and fertility guidance for the deaf through analyzing pedigree and molecular genetic characteristics of the couple who have non-syndromic sensorineural hearing loss (NSHL). METHODS: One of hospitalized congenial deaf couple and family members were included in this study. The wife was twin pregnant woman and her gestational age was 31(+5) pregnant weeks. The DNA was extracted from peripheral blood and umbilical vein blood, respectively. Mutation screening of common deafness genes was performed in pregnant women and other family members. Nine common mutations in four major deafness genes, GJB2 (35delG, 176del16, 235delC, 299delAT), GjB3 (C538T), SLC26A4 (IVS7-2A>G, A2168G) and Mitochondrial 12S rRNA (A1555G, C1494T), were detected simultaneously with a microarray based method. SLC26A4 whole genome sequencing was carried out for the results of the DNA microarray. According to the test results, the couple chose abortion termination of pregnancy twins, and after one year obtained singleton pregnancy by artificial insemination by donor (AID). In week 16 of pregnancy, amniocentesis had been done to collect fetal somatic cell and extract DNA, and then the above tests had been repeated. RESULTS: The couple had SLC26A4 combined heterozygous mutation. Both parents had SLC26A4 single heterozygous mutation. Twin fetuses had SLC26A4 combined heterozygous mutation. The probability of naturally being pregnant and bearing deaf children for the pregnant women was 100%. Fetus obtained by AID had SLC26A4 single heterozygous mutation. After the birth of the baby, her hearing has been normal. CONCLUSIONS: To reduce children with congenital deafness, screening high mutation sites by microarray, combined with pedigree analysis and gene sequencing is effective, and should be used as a routine inspection item for the deaf before marriage and pregnancy. On the basis of genetic testing for the couple with hearing loss, human assisted reproductive technology is a viable option to avoid the birth of infant with hereditary deafness.

19.
Sci Rep ; 4: 6113, 2014 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-25146448

RESUMEN

Studies have investigated the relationship between genetic variants and risk of gestational diabetes mellitus (GDM). However, the results remain inconclusive. The aim of this study was to investigate the association of rs10830963 and rs1387153 variants in melatonin receptor 1B (MTNR1B) and rs1801278 variant in insulin receptor substrate 1 (IRS1) with GDM susceptibility. Electronic database of PubMed, Medline, Embase, and CNKI (China National Knowledge Infrastructure) were searched for relevant studies between 2005 and 2014. The odds ratio (OR) with its 95% confidence interval (CI) were employed to estimate the association. Total ten case-control studies, including 3428 GDM cases and 4637 healthy controls, met the inclusion criteria. Our results showed a significant association between the three genetic variants and GDM risk, rs10830963 with a P-value less than 0.0001, rs1387153 with a P-value of 0.0002, and rs1801278 with a P-value of 0.001. Furthermore, all the genetic models in these three polymorphisms were associated with increased risks of GDM as well (P< = 0.009). In conclusion, our study found that the genetic polymorphisms rs10830963 and rs1387153 in MTNR1B and rs1801278 in IRS1 were associated with an increased risk of developing GDM. However, further studies with gene-gene and gene-environmental interactions should be considered.


Asunto(s)
Diabetes Gestacional/genética , Predisposición Genética a la Enfermedad , Proteínas Sustrato del Receptor de Insulina/genética , Polimorfismo Genético , Receptor de Melatonina MT2/genética , Alelos , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Oportunidad Relativa , Embarazo , Sesgo de Publicación
20.
Guang Pu Xue Yu Guang Pu Fen Xi ; 31(3): 853-7, 2011 Mar.
Artículo en Chino | MEDLINE | ID: mdl-21595255

RESUMEN

The present paper proposes a spectral discrimination method combining spectral information divergence with spectral gradient angle (SID x tan(SGA(pi/2)) which overcomes the shortages of the existing methods which can not take the whole spectral shape and local characteristics into account simultaneously. Using the simulation spectra as input data, according to the interferogram acquirement principle and spectrum recovery algorithm of the temporally and spatially modulated Fourier transform imaging spectrometer (TSMFTIS), we simulated the distortion spectra recovery process of the TMSFTIS in different maximum mix ratio and distinguished the difference between the recovered spectra and the true spectrum by different spectral discrimination methods. The experiment results show that the SID x tan(SGA(pi/2)) can not only identify the similarity of the whole spectral shapes, but also distinguish local differences of the spectral characteristics. A comparative study was conducted among the different discrimination methods. The results have validated that the SID x tan(SGA(pi/2)) has a significant improvement in the discriminatory ability.

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