Specific Recruitment of Antigen-presenting Cells by Chemerin, a Novel Processed Ligand from Human Inflammatory Fluids

Dendritic cells (DCs) and macrophages are professional antigen-presenting cells (APCs) that play key roles in both innate and adaptive immunity. ChemR23 is an orphan G protein–coupled receptor related to chemokine receptors, which is expressed specifically in these cell types. Here we present the characterization of chemerin, a novel chemoattractant protein, which acts through ChemR23 and is abundant in a diverse set of human inflammatory fluids. Chemerin is secreted as a precursor of low biological activity, which upon proteolytic cleavage of its COOH-terminal domain, is converted into a potent and highly specific agonist of ChemR23, the chemerin receptor. Activation of chemerin receptor results in intracellular calcium release, inhibition of cAMP accumulation, and phosphorylation of p42–p44 MAP kinases, through the Gi class of heterotrimeric G proteins. Chemerin is structurally and evolutionary related to the cathelicidin precursors (antibacterial peptides), cystatins (cysteine protease inhibitors), and kininogens. Chemerin was shown to promote calcium mobilization and chemotaxis of immature DCs and macrophages in a ChemR23-dependent manner. Therefore, chemerin appears as a potent chemoattractant protein of a novel class, which requires proteolytic activation and is specific for APCs

Rôle de la thymidylate synthase et de P53 dans la résistance cellulaire au 5-fluorouracile (implications dans la régulation du cycle cellulaire et dans la mise en place de l'apoptose)

NANCY1-SCD Pharmacie-Odontologie (543952101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Radiation could induce p53-independent and cell cycle - Unrelated apoptosis in 5-fluorouracil radiosensitized head and neck carcinoma cells

The effect of chemoresistance induction in radiosensitivity and cellular behavior after irradiation remains misunderstood. This study was designed to understand the relationship between radiation-induced cell cycle arrest, apoptosis, and radiosensitivity in KB cell line and KB3 subline selected after 5-fluorouracil (5FU) exposure. Exposure of KB cells to 5FU led to an increase in radiosensitivity. G 2/M cell cycle arrest was observed in the two cell lines after irradiation. The radioresistant KB cell line reached the maximum arrest two hours before KB3. The cellular exit from this arrest was found to be related to the wild type p53 protein expression induction. After irradiation, only KB3 cell line underwent apoptosis. This apoptosis induction seemed to be independent of G 2/M arrest exit, which was carried out later. The difference in radiosensitivity between KB and KB3 subline may result therefore from both a difference in apoptosis induction and a difference in G 2/M arrest maximum duration. Moreover, 5FU exposure has led to an increase in constitutive p53 protein expression, which may be associated with an increase in basal apoptosis cell fraction. Given the existing correlation between radiosensitivity and the percentage of basal apoptosis, the constitutive p53 protein expression may be related to intrinsic radiosensitivity in our cellular model.SCOPUS: cp.jinfo:eu-repo/semantics/publishe

Constitutive NF-κB activity influences basal apoptosis and radiosensitivity of head-and-neck carcinoma cell lines

Purpose: Nuclear factor-κB (NF-κB) has been implicated in anti-apoptotic gene transactivation, according to its transcriptional activity. The present study was designed to investigate whether constitutive NF-κB activity could modulate basal apoptosis and intrinsic radiosensitivity of KB head-and-neck carcinoma cell line and KB3 subline. The KB3 subline was more radiosensitive (SF2 = 0.48, α = 0.064) than the radioresistant KB parental cell line (SF2 = 0.80, α = 0.114). Methods and Materials: Constitutive NF-κB DNA-binding activity was determined using electrophoretic mobility shift assay. Modulation of NF-κB activity was performed by exposing both cell lines to tumor necrosis factor α or dexamethasone. Apoptotic cell population was analyzed using flow cytometry (annexin V/propidium iodide). Radiosensitivity was assessed from determination of the surviving fraction at 2 Gy (SF2), and α and β parameters were determined using the linear-quadratic model. Results: Constitutive NF-κB activity was found to be significantly lower in KB3 than in KB. KB cell line exposure to dexamethasone significantly decreased NF-κB DNA-binding activity and, consequently, enhanced baseline apoptosis and radiosensitivity (α values: 0.114 vs. 0.052). Conversely, exposure of KB3 cells to tumor necrosis factor α increased NF-κB DNA-binding activity and resulted in a significant decrease (50%) in rate of apoptosis and in radiosensitivity (SF2 values: 0.48 vs. 0.63). Conclusions: Modulation of NF-κB DNA-binding activity influences baseline apoptosis and intrinsic radiosensitivity. © 2001 Elsevier Science Inc.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Activation of GPR54 promotes cell cycle arrest and apoptosis of human tumor cells through a specific transcriptional program not shared by other Gq-coupled receptors.

GPR54 is a receptor for peptides derived from the metastasis suppressor gene KiSS-1. To investigate the intracellular mechanisms involved in the reduction of the metastatic potential of MDA-MB-435S cells expressing GPR54, a time course stimulation by kisspeptin-10 over a period of 25 h was performed using cDNA microarrays. Comparison with the bradykinin B(2) receptor revealed a distinct pattern of gene regulation despite a common coupling to the G(q/11) class of G-proteins. Inhibitors of PLC and PK-C abolished the transcriptional regulation of all tested genes, while an inhibitor of p42/44 affected a subset of genes controlled both by GPR54 and B(2). Among the genes specifically up-regulated by GPR54, we found several proapoptotic genes. Stimulation of GPR54 promoted apoptosis while no significant change was observed after B(2) receptor activation. Our results suggest that the metastasis suppressor properties of GPR54 are mediated in part by cell cycle arrest and induction of apoptosis in malignant cells.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Etude LYMPHOREC. Réponse immunitaire intra-tumorale à la radiothérapie préopératoire pour des cancers du rectum de stades II-III: nouveau paramètre pronostic de la survie des patients

National audienc

Tumoral lymphocyte immune response to preoperative radiotherapy in locally advanced rectal cancer as a prognostic factor for survival: the LYMPHOREC study

Présentation PosterInternational audienceBackground: Short-course preoperative radiotherapy (sc-preopRT) and long-course preoperative radiotherapy (lc-preopRT) followed by total mesorectal excision (TME) are worldwide standards of care in locally advanced T3–4 N0 or N1 rectal adenocarcinoma. It is now well established that the host immune system participates in the elimination of tumor cells and that significant tumor infiltration by T-cells (LT), such as CD8+, is associated with a better prognosis. In colorectal tumors, the infiltration of Treg FoxP3+ is also described as a prognostic factor associated with better survival. We aimed to investigate the impact of the immune response to preoperative RT on progression-free survival (PFS) and overall survival (OS) in rectal cancer managed with TME.Material and Methods: We analyzed data for 237 patients with rectal cancer who underwent TME between 1995 and 2007 after neo-adjuvant treatment with preoperative RT with or without CT in 3 French centers. The LYMPHOREC study was approved by the French national review boards and independent ethics committee (CPP, CCTIRS and the CNIL). Our primary objective was to assess the impact of the immune infiltration of the tumor or tumor site (in cases with complete response) by CD8+ and FoxP3+ lymphocytes after sc-preopRT or lc-preopRT with or without CT on progression-free survival (PFS) and overall survival (OS). Our secondary objectives were to assess changes in the quantities of these lymphocyte infiltrations with respect to the type of preoperative RT (with vs without chemotherapy) or the dose fractionation scheme (≤2Gy vs >2Gy/fraction). These second analyses were performed with 133 patients from whom one biopsy sample was collected. A biopsy-based pretherapeutic lymphocyte infiltration was thus evaluated.Results: In univariate analysis, TNM stage, the delay between surgery and RT, CD8+, FoxP3+ and the ratio CD8+/FoxP3+ were significantly correlated with survival outcomes while chemotherapy as a component of preoperative radiotherapy was not. In multivariate analysis, when adjusted for clinical and treatment-related variables, tumor infiltration by FoxP3 lymphocytes after treatment significantly correlated with PFS (p=0.007). Variations in the CD8/FoxP3 ratio inside the epithelial tissue from before to after preoperative RT correlated with PFS and OS (p=0.049 and p=0.024, respectively). Interestingly, the dose per fraction (<2Gy vs. ≥2Gy) significantly influenced the CD8/FoxP3 ratio after treatment (p=0.027) with a lower ratio with hypofractionated RT.Conclusions: Patients with rectal cancer who had a significant decrease in the CD8/FoxP3 ratio after preoperative radiotherapy had better survival outcomes. The CD8/FoxP3 ratio needs to be validated prospectively. The immune response to preoperative RT may guide physicians in the decision to give adjuvant treatment to patients with rectal cancer

Optimized fractionated radiotherapy with anti-PD-L1 and anti-TIGIT: a promising new combination

International audienc

Challenges in glioblastoma research: focus on the tumor microenvironment

International audienceGlioblastoma (GBM) is the most deadly type of malignant brain tumor, despite extensive molecular analyses of GBM cells. In recent years, the tumor microenvironment (TME) has been recognized as an important player and therapeutic target in GBM. However, there is a need for a full and integrated understanding of the different cellular and molecular components involved in the GBM TME and their interactions for the development of more efficient therapies. In this review, we provide a comprehensive report of the GBM TME, which assembles the contributions of physicians and translational researchers working on brain tumor pathology and therapy in France. We propose a holistic view of the subject by delineating the specific features of the GBM TME at the cellular, molecular, and therapeutic levels