Immunothérapie du cancer : espoirs et réalités

Au cours des deux dernières décennies, l’immunologie des tumeurs a connu un réel bouleversement et un foisonnement de découvertes fondamentales qui se sont traduites en applications cliniques. On peut notamment citer l’identification des antigènes de rejet tumoral et des fondements moléculaires et cellulaires de l’immunogénicité et de la tolérance, la connaissance fine de l’immunité innée, l’élucidation de la biologie des cellules dendritiques et une certaine compréhension des mécanismes d’échappement tumoral à l’immuno-surveillance. Ainsi, l’émergence de nouveaux concepts a fait de l’immunothérapie une quatrième modalité de traitement du cancer après les traitements conventionnels. Les acquis fondamentaux ont facilité la reconceptualisation de l’immunothérapie du cancer, qui a connu un élan majeur en devenant de plus en plus spécifique : au cours des dernières années, l’immunothérapie non spécifique, fondée sur le dopage non spécifique du système immunitaire du patient, a laissé place aux approches vaccinales antitumorales peptidiques et cellulaires. Malgré des résultats encourageants obtenus à partir des modèles expérimentaux et des résultats, certes modestes, obtenus chez les patients, plusieurs obstacles inhérents persistent, notamment celui du décryptage du conflit entre le système immunitaire et le micro-environnement tumoral.The notion that the immune system regulates cancer development is now well established. An overwhelming amount of data from animal models, together with compelling data from human patients, indicate that the immune system is instrumental in scanning and irradicating tumors. Analysis of individuals with congenital or acquired immunodeficiencies or patients undergoing immunosuppressive therapy has documented a highly elevated incidence of virally induced malignancies and cancers compared with immunocompetent individuals [1-3]. During the last decade, thanks to the breakthoughts in understanding the molecular mechanisms responsible for immune activation, the tumor antigen identification, the dendritic cell biology, the immunogenecity of tumors, the immune escape mechanisms, the host-tumor relationship, we are facing a new area of tumor immunotherapy. The basic advances were translated in therapeutical applications and have changed the view of immunotherapy from "a dream scenario" to a clinical fourth modality to cancer treatments. Multiple cancer trials using active immunization with vaccines or adoptive immunotherapy have been conducted with only very limited success. There are still a number of issues that still need to be resolved including a better understanding of immune escape mechanisms. Cancer vaccines continue to be evaluated and may lead to the emergence of clinically useful new treatments. A comprehensive approach to define the intricate molecular program initiated by tumor cells to resist to escape and the immune system of the host may help in breaking down the barriers to a more adapted cancer immunotherapy

Deciphering the unusual HLA-A2/Melan-A/MART-1-specific TCR repertoire in humans.

The Melan-A/MART-1(26-35) antigenic peptide is one of the best studied human tumor-associated antigens. It is expressed in healthy melanocytes and malignant melanoma and is recognized by CD8(+) T cells in the context of the MHC class I molecule HLA-A*0201. While an unusually large repertoire of CD8(+) T cells specific for this antigen has been documented, the reasons for its generation have remained elusive. In this issue of the European Journal of Immunology, Pinto et al. [Eur. J. Immunol. 2014. 44: 2811-2821] uncover one important mechanism by comparing the thymic expression of the Melan-A gene to that in the melanocyte lineage. This study shows that medullary thymic epithelial cells (mTECs) dominantly express a truncated Melan-A transcript, the product of misinitiation of transcription. Consequently, the protein product in mTECs lacks the immunodominant epitope spanning residues 26-35, thus precluding central tolerance to this antigen. In contrast, melanocytes and melanoma tumor cells express almost exclusively the full-length Melan-A transcript, thus providing the target antigen for efficient recognition by HLA-A2-restricted CD8(+) T cells. The frequency of these alternative gene transcription modes may be more common than previously appreciated and may represent an important factor modulating the efficiency of central tolerance induction in the thymus

Three novel NY-ESO-1 epitopes bound to DRB1*0803, DQB1*0401 and DRB1*0901 recognized by CD4 T cells from CHP-NY-ESO-1-vaccinated patients

Three novel NY-ESO-1 CD4 T cell epitopes were identified using PBMC obtained from patients who were vaccinated with a complex of cholesterol-bearing hydrophobized pullulan (CHP) and NY-ESO-1 protein (CHP-NY-ESO-1). The restriction molecules were determined by antibody blocking and using various EBV-B cells with different HLA alleles as APC to present peptides to CD4 T cells. The minimal epitope peptides were determined using various N- and C-termini truncated peptides deduced from 18-mer overlapping peptides originally identified for recognition. Those epitopes were DRB1*0901-restricted NY-ESO-1 87-100. DQB1*0401-restricted NY-ESO-1 95-107 and DRB1*0803-restricted NY-ESO-1 124-134. CD4 T cells used to determine those epitope peptides recognized EBV-B cells or DC that were treated with recombinant NY-ESO-1 protein or NY-ESO-1-expressing tumor cell lysate, suggesting that the epitope peptides are naturally processed. These CD4 T cells showed a cytokine profile with Th1 characteristics. Furthermore, NY-ESO-1 87-100 peptide/HLA-DRB1*0901 tetramer staining was observed. Multiple Th1-type CD4 T cell responses are beneficial for inducing effective anti-tumor responses after NY-ESO-1 protein vaccination

La gestion des connaissances, un outil de performance organisationnelle

RÉSUMÉ: La connaissance est devenue un avantage compétitif indéniable qui permet aux entreprises de se distinguer et de s'imposer sur le marché. Pour ce faire, nous avons procédé à une analyse du contexte économique marqué par I'essor des nouvelles technologies qui ont modifié de manière radicale les moyens de communication. À cet effet, nous avons caractérisé la société de savoir dans laquelle nous nous inscrivons. Nous avons également fait la genèse de la notion d'intelligence économique, son émergence, ses composantes et son rôle dans les politiques publiques. Nous avons établi également un panorama des connaissances à travers lequel ses composantes seront explicitées et avons insisté, par la suite, sur le développement de la capitalisation à travers les systèmes de gestion des connaissances. Nous avons procédé à une enquête quantitative à travers un questionnaire afin d'évaluer nos hypothèses. Dans cette recherche, nous avons opté pour une vision globale et intégratrice de la notion de connaissance. Nous considérons l'ensemble du capital intellectuel, où la connaissance est une étape d'un processus. La connaissance résulte d'un processus d'intégration et d'appropriation par chaque individu. L'objectif de ce travail de recherche est de mettre en exergue la corrélation entre une gestion des connaissances optimale et la performance d'une entreprise. L'organisation qui s'attèle à une gestion des connaissances augmente fortement ses capacités « compétitives ». En effet, ce processus contribue au développement de quatre dimensions : proactive, concurrentielle, protectrice, anticipative qui impactent positivement la performance des organisations. -- Mot(s) clé(s) en français : gestion des connaissances, NTIC, intelligence économique, créativité, interactions sociales, capital intellectuel. -- ABSTRACT: Knowledge has become an undeniable competitive advantage that enables companies to differentiate themselves and succeed in the market. To do this, we conduct an analysis of the economic context marked by the rise of new technologies that have changed dramatically the communication means. To this end, we will characterize the knowledge society in which we subscribe. We also made the genesis of the concept of economic intelligence, its emergence, its components and its role in public policy. We also establish a panorama of knowledge through which its components are explained and we insist later on the development of capitalization through knowledge management systems. We conducted a quantitative survey through a survey to evaluate our hypotheses. In this research, we opted for a global and inclusive vision of the concept of knowledge. We consider the whole intellectual capital, where knowledge is a step in a process. Knowledge is the result of a process of integration and appropriation by each individual. The objective of this research is to highlight the relationship that exists between optimal knowledge management and performance of a company. The organizalion that is striving to knowledge management greatly increases its "competitive" capabilities. Indeed, this process contributes to the development of four dimensions: proactive, competitive, protective, proactive those positively impact the organizations. -- Mot(s) clé(s) en anglais : knowledge management, IT, business intelligence, creativity, social interaction, intellectual capital

Endothelial cells as key determinants of the tumor microenvironment: interaction with tumor cells, extracellular matrix and immune killer cells.

Besides tumor cells, the tumor microenvironment harbors a variety of host-derived cells, such as endothelial cells, fibroblasts, innate and adaptive immune cells. It is a complex and highly dynamic environment, providing very important cues to tumor development and progression. Tumor-associated endothelial cells play a key role in this process. On the one hand, they form tumor-associated (angiogenic) vessels through sprouting from locally preexisting vessels or recruitment of bone marrow-derived endothelial progenitor cells, to provide nutritional support to the growing tumor. On the other hand, they are the interface between circulating blood cells, tumor cells and the extracellular matrix, thereby playing a central role in controlling leukocyte recruitment, tumor cell behavior and metastasis formation. Hypoxia is a critical parameter modulating the tumor microenvironment and endothelial/tumor cell interactions. Under hypoxic stress, tumor cells produce factors that promote tumor angiogenesis, tumor cell motility and metastasis. Among these factors, VEGF, a main angiogenesis modulator, can also play a critical role in the control of immune tolerance. This review discusses some aspects of the role of endothelial cells within tumor microenvironment and emphasizes their interaction with tumor cells, the extracellular matrix and with immune killer cells. We will also address the role played by circulating endothelial progenitor cells and illustrate their features and mechanism of recruitment to the tumor microenvironment and their role in tumor angiogenesis

A ras-Mutated Peptide Targeted by CTL Infiltrating a Human Melanoma Lesion 1

International audienceAgs derived from commonly mutated oncogenic proteins seem ideally suited as targets for tumor immunotherapy. Nonetheless, only a few mutated epitopes efficiently presented by human tumors have thus far been identified. We describe here an approach to identify such epitopes. This approach involves: 1) identifying tumors expressing a ras mutation and isolating the tumor-infiltrating lymphocytes (TIL); 2) transfecting COS cells to induce expression of unknown mutated peptides in the context of a patient's HLA class I molecules; and 3) screening epitope recognition by using TIL from the tumors expressing a ras mutation. By using this approach, there appeared to be a N-ras mutation (a glutamine-to-arginine exchange at residue 61 (Q61R)), detected in a melanoma lesion, which was recognized specifically by the autologous TIL in the HLA-A*0101 context. The ras peptide 55-64 Q61R was the epitope of these TIL and was regularly presented by Q61R-mutated HLA-A*0101 ؉ melanoma cell lines. This peptide and its wild-type homolog (55-64 wt) bound to HLA-A*0101 with similar affinities. However, only the mutated peptide could induce specific CTL expansion from PBL. All the CTL clones specific to the mutated peptide, failed to recognize the wild-type sequence on both COS and melanoma cells. These data thus show that oncogenic protein mutations can create shared tumor-specific CTL epitopes, efficiently presented by tumor cells, and that screening for oncogene-transfected COS cell recognition by TIL (from tumors containing mutations) is a powerful approach for the identification of these epitopes

Endothelial cells as key determinants of the tumor microenvironment: interaction with tumor cells, extracellular matrix and immune killer cells.

International audienceBesides tumor cells, the tumor microenvironment harbors a variety of host-derived cells, such as endothelial cells, fibroblasts, innate and adaptive immune cells. It is a complex and highly dynamic environment, providing very important cues to tumor development and progression. Tumor-associated endothelial cells play a key role in this process. On the one hand, they form tumor-associated (angiogenic) vessels through sprouting from locally preexisting vessels or recruitment of bone marrow-derived endothelial progenitor cells, to provide nutritional support to the growing tumor. On the other hand, they are the interface between circulating blood cells, tumor cells and the extracellular matrix, thereby playing a central role in controlling leukocyte recruitment, tumor cell behavior and metastasis formation. Hypoxia is a critical parameter modulating the tumor microenvironment and endothelial/tumor cell interactions. Under hypoxic stress, tumor cells produce factors that promote tumor angiogenesis, tumor cell motility and metastasis. Among these factors, VEGF, a main angiogenesis modulator, can also play a critical role in the control of immune tolerance. This review discusses some aspects of the role of endothelial cells within tumor microenvironment and emphasizes their interaction with tumor cells, the extracellular matrix and with immune killer cells. We will also address the role played by circulating endothelial progenitor cells and illustrate their features and mechanism of recruitment to the tumor microenvironment and their role in tumor angiogenesis

Soluble HLA-I/Peptide Monomers Mediate Antigen-Specific CD8 T Cell Activation through Passive Peptide Exchange with Cell-Bound HLA-I Molecules

International audienceAccumulating evidence that serum levels of soluble class I HLA molecules (sHLA-I) can, under various pathological conditions, correlate with disease stage and/or patient survival, has stimulated interest in defining whether sHLA-I can exert immunological functions. However, despite a mounting number of publications suggesting the ability of sHLA-I to affect immune effectors in vitro, the precise underlying mechanism still remains controversial. In this article, we address potential functions of both classical and nonclassical sHLA-I, using soluble recombinant HLA-I/peptide monomers, and clearly demonstrate their ability to trigger Ag-specific activation of CD8 T cells in vitro. Furthermore, we provide strong evidence that this behavior results from the passive transfer of peptides from monomers to T cell-bound HLA-I molecules, allowing for fratricide representation and activation. Hence, we proposed a unifying model of T cell activation by HLA-I/peptide monomers, reappraising the potential involvement of sHLA-I molecules in the immune response

The antiangiogenic activtivity of IL-12 is increased in iNOS-/- mice and involves NK cells

International audienceWe have previously reported that the in vivo transfer of murine interleukin-12 (IL-12) gene using a Semliki Forest virus vector induced tumor regression through inhibition of tumor blood vessel formation. To examine whether IL-12 anti-angiogenic activity interferes with the NO pathway, we used inducible nitric oxide synthase-deficient mice (iNOS−/−) and demonstrated that the anti-tumor effect of IL-12 is more pronounced in these mice. In addition, despite the increased level of intratumoral VEGF in iNOS−/− mice, IL-12 induced a stronger inhibition of blood vessel formation. Histological analysis of SFV-IL-12-treated tumors showed an increase in natural killer (NK) perivascular infiltration in iNOS−/− as compared to control mice. In vitro IL-12-stimulated murine splenic NK cells displayed significant killing activity towards established murine endothelial cells used as targets. These studies indicate that the anti-angiogenic activity of IL-12 interferes with iNOS pathway and involves NK cell recruitment