Mirebel – Château Reculet-les-Mirebel

Lors des premiers relevés de masse du château de Mirebel (Jura), au regard de la topographie très escarpée des lieux (éperon rocheux de 400 m sur 20 m), s'est posée la question de l'emplacement de l'entrée principale de la forteresse, compte tenu de l'existence d'un chemin ancien partant de l'église. En juillet 2008, grâce au dégagement du pavage du chemin et d'une large ornière, la fouille a permis de confirmer qu'il s'agissait bien du chemin d'accès principal au château. La campagne de sond..

Restrictions on the lifetime of sterile neutrinos from primordial nucleosynthesis

We analyze the influence of decaying sterile neutrinos with the masses in the range 1-140 MeV on the primordial Helium-4 abundance, explicitly solving the Boltzmann equations for all particle species, taking into account neutrino flavour oscillations, and paying special attention to systematic uncertainties. We show that the Helium abundance depends only on the sterile neutrino lifetime and not on the way the active-sterile mixing is distributed between flavours, and derive an upper bound on the lifetime. We also demonstrate that the recent results of Izotov & Thuan [arXiv:1001.4440], who find 2sigma higher than predicted by the standard primordial nucleosynthesis value of Helium-4 abundance, are consistent with the presence in the plasma of sterile neutrinos with the lifetime 0.01-2 seconds. The decay of these particles perturbs the spectra of (decoupled) neutrinos and heats photons, changing the ratio of neutrino to photon energy density, that can be interpreted as extra neutrino species at the recombination epoch.Comment: 17 pp. + Appendices. Analysis of deuterium bounds and more accurate account of CMB bounds on Helium-4 is added. Final version to appear in JCA

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

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

Définition de nouveaux indicateurs d'endommagement en fatigue cyclique pour les CMC : vers la prévision de la durée de vie

Les matériaux composites à matrice céramique (CMC) semblent être des matériaux très prometteurs pour les nouvelles générations de propulseurs civils du fait de leur faible densité et leur grande ténacité en température. Il est donc nécessaire de connaitre et de comprendre les mécanismes d’endommagement de ce type de matériau, et particulièrement pour des sollicitations de longues durées. Dans ce but des essais de fatigue cyclique et statique sont réalisés en température (T=450°C). En raison de la complexité des modes d’endommagement, il est indispensable de développer des moyens de suivi des mécanismes d’endommagement en temps réel. Cette étude propose d’utiliser l’émission acoustique comme indicateur d’endommagement, au travers de deux approches. D’une part l’identification de la signature acoustique d’un mécanisme d’endommagement permet sa détection en temps réel et l’évaluation de sa criticité. D’autre part, en considérant l’énergie acoustique de manière globale et en la comparant à l’énergie mécanique, il est possible de déterminer en temps réel différents niveaux d’endommagement caractéristiques du matériau

Immunopeptidomics of colorectal cancer organoids reveals a sparse HLA class I neoantigen landscape and no increase in neoantigens with interferon or MEK-inhibitor treatment.

Patient derived organoids (PDOs) can be established from colorectal cancers (CRCs) as in vitro models to interrogate cancer biology and its clinical relevance. We applied mass spectrometry (MS) immunopeptidomics to investigate neoantigen presentation and whether this can be augmented through interferon gamma (IFNγ) or MEK-inhibitor treatment. Four microsatellite stable PDOs from chemotherapy refractory and one from a treatment naïve CRC were expanded to replicates with 100 million cells each, and HLA class I and class II peptide ligands were analyzed by MS. We identified an average of 9936 unique peptides per PDO which compares favorably against published immunopeptidomics studies, suggesting high sensitivity. Loss of heterozygosity of the HLA locus was associated with low peptide diversity in one PDO. Peptides from genes without detectable expression by RNA-sequencing were rarely identified by MS. Only 3 out of 612 non-silent mutations encoded for neoantigens that were detected by MS. In contrast, computational HLA binding prediction estimated that 304 mutations could generate neoantigens. One hundred ninety-six of these were located in expressed genes, still exceeding the number of MS-detected neoantigens 65-fold. Treatment of four PDOs with IFNγ upregulated HLA class I expression and qualitatively changed the immunopeptidome, with increased presentation of IFNγ-inducible genes. HLA class II presented peptides increased dramatically with IFNγ treatment. MEK-inhibitor treatment showed no consistent effect on HLA class I or II expression or the peptidome. Importantly, no additional HLA class I or II presented neoantigens became detectable with any treatment. Only 3 out of 612 non-silent mutations encoded for neoantigens that were detectable by MS. Although MS has sensitivity limits and biases, and likely underestimated the true neoantigen burden, this established a lower bound of the percentage of non-silent mutations that encode for presented neoantigens, which may be as low as 0.5%. This could be a reason for the poor responses of non-hypermutated CRCs to immune checkpoint inhibitors. MEK-inhibitors recently failed to improve checkpoint-inhibitor efficacy in CRC and the observed lack of HLA upregulation or improved peptide presentation may explain this

ILC2-modulated T cell-to-MDSC balance is associated with bladder cancer recurrence.

Non-muscle-invasive bladder cancer (NMIBC) is a highly recurrent tumor despite intravesical immunotherapy instillation with the bacillus Calmette-Guérin (BCG) vaccine. In a prospective longitudinal study, we took advantage of BCG instillations, which increase local immune infiltration, to characterize immune cell populations in the urine of patients with NMIBC as a surrogate for the bladder tumor microenvironment. We observed an infiltration of neutrophils, T cells, monocytic myeloid-derived suppressor cells (M-MDSCs), and group 2 innate lymphoid cells (ILC2). Notably, patients with a T cell-to-MDSC ratio of less than 1 showed dramatically lower recurrence-free survival than did patients with a ratio of greater than 1. Analysis of early and later time points indicated that this patient dichotomy existed prior to BCG treatment. ILC2 frequency was associated with detectable IL-13 in the urine and correlated with the level of recruited M-MDSCs, which highly expressed IL-13 receptor α1. In vitro, ILC2 were increased and potently expressed IL-13 in the presence of BCG or tumor cells. IL-13 induced the preferential recruitment and suppressive function of monocytes. Thus, the T cell-to-MDSC balance, associated with a skewing toward type 2 immunity, may predict bladder tumor recurrence and influence the mortality of patients with muscle-invasive cancer. Moreover, these results underline the ILC2/IL-13 axis as a targetable pathway to curtail the M-MDSC compartment and improve bladder cancer treatment

Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data.

Immune cells infiltrating tumors can have important impact on tumor progression and response to therapy. We present an efficient algorithm to simultaneously estimate the fraction of cancer and immune cell types from bulk tumor gene expression data. Our method integrates novel gene expression profiles from each major non-malignant cell type found in tumors, renormalization based on cell-type-specific mRNA content, and the ability to consider uncharacterized and possibly highly variable cell types. Feasibility is demonstrated by validation with flow cytometry, immunohistochemistry and single-cell RNA-Seq analyses of human melanoma and colorectal tumor specimens. Altogether, our work not only improves accuracy but also broadens the scope of absolute cell fraction predictions from tumor gene expression data, and provides a unique novel experimental benchmark for immunogenomics analyses in cancer research (http://epic.gfellerlab.org)

NNAlign_MA; MHC peptidome deconvolution for accurate MHC binding motif characterization and improved T cell epitope predictions

The set of peptides presented on a cell's surface by MHC molecules is known as the immunopeptidome. Current mass spectrometry technologies allow for identification of large peptidomes, and studies have proven these data to be a rich source of information for learning the rules of MHC-mediated antigen presentation. Immunopeptidomes are usually poly-specific, containing multiple sequence motifs matching the MHC molecules expressed in the system under investigation. Motif deconvolution -the process of associating each ligand to its presenting MHC molecule(s)- is therefore a critical and challenging step in the analysis of MS-eluted MHC ligand data. Here, we describe NNAlign_MA, a computational method designed to address this challenge and fully benefit from large, poly-specific data sets of MS-eluted ligands. NNAlign_MA simultaneously performs the tasks of (1) clustering peptides into individual specificities; (2) automatic annotation of each cluster to an MHC molecule; and (3) training of a prediction model covering all MHCs present in the training set. NNAlign_MA was benchmarked on large and diverse data sets, covering class I and class II data. In all cases, the method was demonstrated to outperform state-of-the-art methods, effectively expanding the coverage of alleles for which accurate predictions can be made, resulting in improved identification of both eluted ligands and T-cell epitopes. Given its high flexibility and ease of use, we expect NNAlign_MA to serve as an effective tool to increase our understanding of the rules of MHC antigen presentation and guide the development of novel T-cell-based therapeutics