146 research outputs found

    Tumor-Associated Macrophages in Bladder Cancer: Biological Role, Impact on Therapeutic Response and Perspectives for Immunotherapy.

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    Tumor-associated macrophages (TAMs) are one of the most abundant infiltrating immune cells of solid tumors. Despite their possible dual role, i.e., pro- or anti-tumoral, there is considerable evidence showing that the accumulation of TAMs promotes tumor progression rather than slowing it. Several strategies are being developed and clinically tested to target these cells. Bladder cancer (BCa) is one of the most common cancers, and despite heavy treatments, including immune checkpoint inhibitors (ICIs), the overall patient survival for advanced BCa is still poor. TAMs are present in bladder tumors and play a significant role in BCa development. However, few investigations have analyzed the effect of targeting TAMs in BCa. In this review, we focus on the importance of TAMs in a cancerous bladder, their association with patient outcome and treatment efficiency as well as on how current BCa treatments impact these cells. We also report different strategies used in other cancer types to develop new immunotherapeutic strategies with the aim of improving BCa management through TAMs targeting

    Inhibitory Receptors Beyond T Cell Exhaustion.

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    Inhibitory receptors (iRs) are frequently associated with "T cell exhaustion". However, the expression of iRs is also dependent on T cell differentiation and activation. Therapeutic blockade of various iRs, also referred to as "checkpoint blockade", is showing -unprecedented results in the treatment of cancer patients. Consequently, the clinical potential in this field is broad, calling for increased research efforts and rapid refinements in the understanding of iR function. In this review, we provide an overview on the significance of iR expression for the interpretation of T cell functionality. We summarize how iRs have been strongly associated with "T cell exhaustion" and illustrate the parallel evidence on the importance of T cell differentiation and activation for the expression of iRs. The differentiation subsets of CD8 T cells (naïve, effector, and memory cells) show broad and inherent differences in iR expression, while activation leads to strong upregulation of iRs. Therefore, changes in iR expression during an immune response are often concomitant with T cell differentiation and activation. Sustained expression of iRs in chronic infection and in the tumor microenvironment likely reflects a specialized T cell differentiation. In these situations of prolonged antigen exposure and chronic inflammation, T cells are "downtuned" in order to limit tissue damage. Furthermore, we review the novel "checkpoint blockade" treatments and the potential of iRs as biomarkers. Finally, we provide recommendations for the immune monitoring of patients to interpret iR expression data combined with parameters of activation and differentiation of T cells

    Caractérisation sous système d'information géographique des incendies de forêts : l'exemple du Liban.

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    Cette étude a été conduite dans le contexte de la définition d'une stratégie de défense contre les incendies au Liban. On a procédé à la création d'un système de gestion des incendies par circonscription foncière. L'analyse statistique et spatiale (sous SIG) des données recueillies sur les incendies au cours d'une période de 20 ans (1983-2003) nous a permis d'établir des cartes de récurrence des feux, de définir les types de peuplements les plus affectés et de déterminer la période critique et les causes probables de leur occurrence

    Cellular localisation of VvRops and VvRabA5e, small GTPases developmentally regulated in grape berries

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    VvRops, in particular VvRop9, and VvRabA5e are small GTPases which are developmentally regulated in grape berries. In an attempt to help elucidate the role of these proteins during fruit development and ripening, we investigated their localisation in the fruit by immunocytofluorescence. These proteins were observed at a perinuclear location, at cell periphery and around vesicles. In particular VvRops were found to be located in the nucleus and likely on the plasma membrane. VvRop9 and VvRabA5e cDNAs were introduced separately into S. cerevisiae mutants with RHO1 and YPT31/YPT32 defective genes respectively. Neither cDNAs could complement these temperature-sensitive mutants, suggesting that the functions of the VvRop9 and VvRabA5e genes in grapevine likely differ from the functions of RHO1 and YPT31/YPT32 genes in yeast.

    29 th Annual meeting of the Society for Immunotherapy of Cancer (SITC)

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    The 29 th annual meeting of the Society for Immunotherapy of Cancer (SITC) was held November 7-9, 2014 in National Harbor, MD and was organized by Dr. Arthur A. Hurwitz (National Cancer Institute), Dr. Kim A. Margolin (Stanford University), Dr. Daniel E. Speiser (Ludwig Center for Cancer Research, University of Lausanne) and Dr. Walter J. Urba (Earle A. Chiles Research Institute, Providence Cancer Center). This meeting included over 1,600 registered participants from 28 separate countries, making it the largest SITC meeting held to date. It highlighted significant worldwide progress in the development and application of cancer immunology to the practice of clinical oncology, including advances in diagnosis, prognosis and therapy, utilizing several immunological pathways and mechanisms for a variety of oncologic conditions. Presentations and posters demonstrated that many concepts that had been pursued preclinically in the past are now being translated into clinical practice, with clear benefits for patients

    c-Maf enforces cytokine production and promotes memory-like responses in mouse and human type 2 innate lymphoid cells

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    Group-2 innate lymphoid cells (ILC2s), which are involved in type 2 inflammatory diseases such as allergy, can exhibit immunological memory, but the basis of this ILC2 "trained immunity" has remained unclear. Here, we found that stimulation with IL-33/IL-25 or exposure to the allergen papain induces the expression of the transcription factor c-Maf in mouse ILC2s. Chronic papain exposure results in high production of IL-5 and IL-13 cytokines and lung eosinophil recruitment, effects that are blocked by c-Maf deletion in ILCs. Transcriptomic analysis revealed that knockdown of c-Maf in ILC2s suppresses expression of type 2 cytokine genes, as well as of genes linked to a memory-like phenotype. Consistently, c-Maf was found highly expressed in human adult ILC2s but absent in cord blood and required for cytokine production in isolated human ILC2s. Furthermore, c-Maf-deficient mouse or human ILC2s failed to exhibit strengthened (“trained”) responses upon repeated challenge. Thus, the expression of c-Maf is indispensable for optimal type 2 cytokine production and proper memory-like responses in group-2 innate lymphoid cells

    Inflammatory B cells correlate with failure to checkpoint blockade in melanoma patients.

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    The understanding of the role of B cells in patients with solid tumors remains insufficient. We found that circulating B cells produced TNFα and/or IL-6, associated with unresponsiveness and poor overall survival of melanoma patients treated with anti-CTLA4 antibody. Transcriptome analysis of B cells from melanoma metastases showed enriched expression of inflammatory response genes. Publicly available single B cell data from the tumor microenvironment revealed a negative correlation between TNFα expression and response to immune checkpoint blockade. These findings suggest that B cells contribute to tumor growth via the production of inflammatory cytokines. Possibly, these B cells are different from tertiary lymphoid structure-associated B cells, which have been described to correlate with favorable clinical outcome of cancer patients. Further studies are required to identify and characterize B cell subsets and their functions promoting or counteracting tumor growth, with the aim to identify biomarkers and novel treatment targets

    Immuno-Transcriptomic Profiling of Blood and Tumor Tissue Identifies Gene Signatures Associated with Immunotherapy Response in Metastatic Bladder Cancer.

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    Blood-based biomarkers represent ideal candidates for the development of non-invasive immuno-oncology-based assays. However, to date, no blood biomarker has been validated to predict clinical responses to immunotherapy. In this study, we used next-generation sequencing (RNAseq) on bulk RNA extracted from whole blood and tumor samples in a pre-clinical MIBC mouse model. We aimed to identify biomarkers associated with immunotherapy response and assess the potential application of simple non-invasive blood biomarkers as a therapeutic decision-making assay compared to tissue-based biomarkers. We established that circulating immune cells and the tumor microenvironment (TME) display highly organ-specific transcriptional responses to ICIs. Interestingly, in both, a common lymphocytic activation signature can be identified associated with the efficient response to immunotherapy, including a blood-specific CD8+ T cell activation/proliferation signature which predicts the immunotherapy response

    Identification of candidate genes for drought tolerance in coffee by high-throughput sequencing in the shoot apex of different Coffea arabica cultivars.

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    BACKGROUND: Drought is a widespread limiting factor in coffee plants. It affects plant development, fruit production, bean development and consequently beverage quality. Genetic diversity for drought tolerance exists within the coffee genus. However, the molecular mechanisms underlying the adaptation of coffee plants to drought are largely unknown. In this study, we compared the molecular responses to drought in two commercial cultivars (IAPAR59, drought-tolerant and Rubi, drought-susceptible) of Coffea arabica grown in the field under control (irrigation) and drought conditions using the pyrosequencing of RNA extracted from shoot apices and analysing the expression of 38 candidate genes. RESULTS: Pyrosequencing from shoot apices generated a total of 34.7 Mbp and 535,544 reads enabling the identification of 43,087 clusters (41,512 contigs and 1,575 singletons). These data included 17,719 clusters (16,238 contigs and 1,575 singletons) exclusively from 454 sequencing reads, along with 25,368 hybrid clusters assembled with 454 sequences. The comparison of DNA libraries identified new candidate genes (n = 20) presenting differential expression between IAPAR59 and Rubi and/or drought conditions. Their expression was monitored in plagiotropic buds, together with those of other (n = 18) candidates genes. Under drought conditions, up-regulated expression was observed in IAPAR59 but not in Rubi for CaSTK1 (protein kinase), CaSAMT1 (SAM-dependent methyltransferase), CaSLP1 (plant development) and CaMAS1 (ABA biosynthesis). Interestingly, the expression of lipid-transfer protein (nsLTP) genes was also highly up-regulated under drought conditions in IAPAR59. This may have been related to the thicker cuticle observed on the abaxial leaf surface in IAPAR59 compared to Rubi. CONCLUSIONS: The full transcriptome assembly of C. arabica, followed by functional annotation, enabled us to identify differentially expressed genes related to drought conditions. Using these data, candidate genes were selected and their differential expression profiles were confirmed by qPCR experiments in plagiotropic buds of IAPAR59 and Rubi under drought conditions. As regards the genes up-regulated under drought conditions, specifically in the drought-tolerant IAPAR59, several corresponded to orphan genes but also to genes coding proteins involved in signal transduction pathways, as well as ABA and lipid metabolism, for example. The identification of these genes should help advance our understanding of the genetic determinism of drought tolerance in coffee
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