Antigen quality determines the efficiency of antitumor immune responses generated in the absence of regulatory T cells

The observation that depletion or inhibition of regulatory T cells (Tregs) unleashes efficient antitumor effector immune responses that can lead to tumor eradication in mice has opened new perspectives for the development of cancer immunotherapy. The quality and overall efficiency of the effector immune responses induced in the absence of Tregs seem to depend on multiple factors that determine the result of a battle involving effector T cells (Teffs), Tregs and tumor cells. In this study, we investigated the quality of tumor-associated antigens (TAAs) as one such factor. We show that the presence of a strong dominant antigen is required for the induction of effector responses capable of tumor eradication in the absence of Tregs. The sole addition of a dominant antigen on tumor cells does not change tumor growth in unmanipulated mice, but improves tumor eradication rate from a few to almost 100% in the absence of Tregs. This eradication can be shown to result from the recruitment and activation of specific Teffs recognizing this antigen. We also show that the presence of such dominant antigens has the side effect of restricting the breadth of the immune response to other TAAs, which could favor the generation of escape mutant by tumor editing. Taken together, our results highlight the potential, and some requirements for cancer immunotherapy based on Treg depletion. They also show that, ultimately, tumor fate depends on multiple factors that should all be taken into consideration for the design of more efficient immunotherapy

Complement as a biological tool to control tumor growth

Deposits of complement components have been documented in several human tumors suggesting a potential involvement of the complement system in tumor immune surveillance. In vitro and in vivo studies have revealed a double role played by this system in tumor progression. Complement activation in the cancer microenvironment has been shown to promote cancer growth through the release of the chemotactic peptide C5a recruiting myeloid suppressor cells. There is also evidence that tumor progression can be controlled by complement activated on the surface of cancer cells through one of the three pathways of complement activation. The aim of this review is to discuss the protective role of complement in cancer with special focus on the beneficial effect of complement-fixing antibodies that are efficient activators of the classical pathway and contribute to inhibit tumor expansion as a result of MAC-mediated cancer cell killing and complement-mediated inflammatory process. Cancer cells are heterogeneous in their susceptibility to complement-induced killing that generally depends on stable and relatively high expression of the antigen and the ability of therapeutic antibodies to activate complement. A new generation of monoclonal antibodies are being developed with structural modification leading to hexamer formation and enhanced complement activation. An important progress in cancer immunotherapy has been made with the generation of bispecific antibodies targeting tumor antigens and able to neutralize complement regulators overexpressed on cancer cells. A great effort is being devoted to implementing combined therapy of traditional approaches based on surgery, chemotherapy and radiotherapy and complement-fixing therapeutic antibodies. An effective control of tumor growth by complement is likely to be obtained on residual cancer cells following conventional therapy to reduce the tumor mass, prevent recurrences and avoid disabilities

Alternative Antigen Processing for MHC Class I: Multiple Roads Lead to Rome

The well described conventional antigen processing pathway is accountable for most peptides that end up in MHC class I molecules at the cell surface. These peptides experienced liberation by the proteasome and transport by the peptide transporter TAP. However, there are multiple roads that lead to Rome, illustrated by the increasing number of alternative processing pathways that have been reported during last years. Interestingly, TAP-deficient individuals do not succumb to viral infections, suggesting that CD8 T cell immunity is sufficiently supported by alternative TAP-independent processing pathways. To date, a diversity of viral and endogenous TAP-independent peptides have been identified in the grooves of different MCH class I alleles. Some of these peptides are not displayed by normal TAP-positive cells and we therefore called them TEIPP, for ‘T-cell epitopes associated with impaired peptide processing’. TEIPPs are hidden self-antigens, are derived from normal housekeeping proteins and are processed via unconventional processing pathways. Per definition, TEIPPs are presented via TAP-independent pathways, but recent data suggest that part of this repertoire still depend on proteasome and metalloprotease activity. An exception is the C-terminal peptide of the ER-membrane spanning ceramide synthase Trh4 that is surprisingly liberated by the signal peptide peptidase (SPP), the proteolytic enzyme involved in cleaving leader sequences. The intramembrane cleaving SPP is thereby an important contributor of TAP-independent peptides. Its family members, like the Alzheimer’s related presenilins, might as well, according to our preliminary data. Finally, alternative peptide routing is an emerging field and includes processes like the unfolded protein response, the ER-associated degradation and autophagy-associated vesicular pathways. These data convince us that there is a world to be discovered in the field of unconventional antigen processing

Cell Adhesion Molecules and Their Roles and Regulation in the Immune and Tumor Microenvironment

The immune system and cancer have a complex relationship with the immune system playing a dual role in tumor development. The effector cells of the immune system can recognize and kill malignant cells while immune system-mediated inflammation can also promote tumor growth and regulatory cells suppress the anti-tumor responses. In the center of all anti-tumor responses is the ability of the immune cells to migrate to the tumor site and to interact with each other and with the malignant cells. Cell adhesion molecules including receptors of the immunoglobulin superfamily and integrins are of crucial importance in mediating these processes. Particularly integrins play a vital role in regulating all aspects of immune cell function including immune cell trafficking into tissues, effector cell activation and proliferation and the formation of the immunological synapse between immune cells or between immune cell and the target cell both during homeostasis and during inflammation and cancer. In this review we discuss the molecular mechanisms regulating integrin function and the role of integrins and other cell adhesion molecules in immune responses and in the tumor microenvironment. We also describe how malignant cells can utilize cell adhesion molecules to promote tumor growth and metastases and how these molecules could be targeted in cancer immunotherapy.Peer reviewe

Le mobilier céramique gaulois de la nécropole Avicenne

The morpho-technological study of ceramic is one of the way of defining a chrono-cultural region. Thanks to morphological and technological methods (petrography, radiography…), a study of a large scale has been conducted on the ceramic of Bobigny. The analysis of this significant set gave the opportunity to get a new view on the potery production of the central area of the Ile-de-France, during the second Iron Age. It underlines such socio-culturals practices

Recent Advances in Targeting CD8 T-Cell Immunity for More Effective Cancer Immunotherapy

Recent advances in cancer treatment have emerged from new immunotherapies targeting T-cell inhibitory receptors, including cytotoxic T-lymphocyte associated antigen (CTLA)-4 and programmed cell death (PD)-1. In this context, anti-CTLA-4 and anti-PD-1 monoclonal antibodies have demonstrated survival benefits in numerous cancers, including melanoma and non-small-cell lung carcinoma. PD-1-expressing CD8+ T lymphocytes appear to play a major role in the response to these immune checkpoint inhibitors (ICI). Cytotoxic T lymphocytes (CTL) eliminate malignant cells through recognition by the T-cell receptor (TCR) of specific antigenic peptides presented on the surface of cancer cells by major histocompatibility complex class I/beta-2-microglobulin complexes, and through killing of target cells, mainly by releasing the content of secretory lysosomes containing perforin and granzyme B. T-cell adhesion molecules and, in particular, lymphocyte-function-associated antigen-1 and CD103 integrins, and their cognate ligands, respectively, intercellular adhesion molecule 1 and E-cadherin, on target cells, are involved in strengthening the interaction between CTL and tumor cells. Tumor-specific CTL have been isolated from tumor-infiltrating lymphocytes and peripheral blood lymphocytes (PBL) of patients with varied cancers. TCRβ-chain gene usage indicated that CTL identified in vitro selectively expanded in vivo at the tumor site compared to autologous PBL. Moreover, functional studies indicated that these CTL mediate human leukocyte antigen class I-restricted cytotoxic activity toward autologous tumor cells. Several of them recognize truly tumor-specific antigens encoded by mutated genes, also known as neoantigens, which likely play a key role in antitumor CD8 T-cell immunity. Accordingly, it has been shown that the presence of T lymphocytes directed toward tumor neoantigens is associated with patient response to immunotherapies, including ICI, adoptive cell transfer, and dendritic cell-based vaccines. These tumor-specific mutation-derived antigens open up new perspectives for development of effective second-generation therapeutic cancer vaccines

Gellainville (Centre-Eure-et-Loir) : "Les Beaumonts" construction de locaux d'activités : rapport de diagnostic

La prescription et la réalisation d'un nouveau diagnostic archéologique dans la zone d'activité de Chartres - Gellainville, sur les 6,5 ha du projet d'aménagement de la SAS «les Beaumonts)) à Gellainville, a permis de collecter des informations archéologiques importantes qui viennent compléter un contexte déjà riche.Une présence humaine durant la Préhistoire, est attestée depuis le Paléolithique, dans cette zone. Elle est à nouveau confirmée, sur ce diagnostic, par la découverte de mobilier de silex épars et provenant de quelques structures creusées, dans la partie méridionale. De nombreux vestiges protohistoriques, attribués à La Tène, sont implantés aux «Beaumonts» dans la moitié septentrionale de l'emprise. Ils se présentent comme un dense réseau de fossés, qui atteste de l'existence d'un ou plusieurs enclos quadrangulaires cloisonnés. Des traces de bâtiments sur poteaux, de structures en creux et de silos indiquent une vocation exploitation agricole pour ces installations. Au même emplacement, s'installe un établissement agricole gallo-romain, au cours du premier siècle de notre ère, de type petite villa sur son "ancêtre" gaulois, ce qui indique une permanence de la fonction agraire de l'occupation aux "Beaumonts". Ce changement de style s'accompagne également d'une modification nette des axes organisateurs du site. La durée d'occupation durant l'antiquité ne paraît, cependant, pas se poursuivre au-delà du Haut Empire, en l'état des données du diagnostic. Enfin, le sud de I’ emprise a conservé, avec un petit fossé, une trace ténue du parcellaire moderne

Senonches (Centre - Eure-et-Loir). Projet d'aménagement du logis du château. Etude des parements extérieurs: Rapport de diagnostic archéologique

Last part of an archaeological trial in the manor house of the castle of Senonches (France, Eure-et-Loir), having led to the discovery of latrines and new conclusions about the chronology of this hous and the curtain wallDernière tranche du diagnostic sur le logis du château de Senonches (Eure-et-Loir), ayant permis la découverte de latrines et de proposer une chronologie détaillée de la construction de l'enceinte et du logi

Eléments de chronologie de la bourgade artisanale de Bobigny (Seine-Saint-Denis)

International audienc

Gellainville (Centre-Eure-et-Loir) : "Les Beaumonts" construction de locaux d'activités : rapport de diagnostic

La prescription et la réalisation d'un nouveau diagnostic archéologique dans la zone d'activité de Chartres - Gellainville, sur les 6,5 ha du projet d'aménagement de la SAS «les Beaumonts)) à Gellainville, a permis de collecter des informations archéologiques importantes qui viennent compléter un contexte déjà riche.Une présence humaine durant la Préhistoire, est attestée depuis le Paléolithique, dans cette zone. Elle est à nouveau confirmée, sur ce diagnostic, par la découverte de mobilier de silex épars et provenant de quelques structures creusées, dans la partie méridionale. De nombreux vestiges protohistoriques, attribués à La Tène, sont implantés aux «Beaumonts» dans la moitié septentrionale de l'emprise. Ils se présentent comme un dense réseau de fossés, qui atteste de l'existence d'un ou plusieurs enclos quadrangulaires cloisonnés. Des traces de bâtiments sur poteaux, de structures en creux et de silos indiquent une vocation exploitation agricole pour ces installations. Au même emplacement, s'installe un établissement agricole gallo-romain, au cours du premier siècle de notre ère, de type petite villa sur son "ancêtre" gaulois, ce qui indique une permanence de la fonction agraire de l'occupation aux "Beaumonts". Ce changement de style s'accompagne également d'une modification nette des axes organisateurs du site. La durée d'occupation durant l'antiquité ne paraît, cependant, pas se poursuivre au-delà du Haut Empire, en l'état des données du diagnostic. Enfin, le sud de I’ emprise a conservé, avec un petit fossé, une trace ténue du parcellaire moderne