WorldCat Identities

Adotevi, Olivier (1965-....).

Overview
Works: 29 works in 41 publications in 2 languages and 51 library holdings
Roles: Opponent, Thesis advisor, Other, Contributor, Author, htt, 956
Classifications: QR181, 616.079
Publication Timeline
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Most widely held works by Olivier Adotevi
Immunothérapie des cancers au troisième millénaire by L Zitvogel( )

2 editions published in 2021 in French and held by 10 WorldCat member libraries worldwide

La vaccination antitumorale avance avec un vaccin cellulaire autologue (à base de cellules dendritiques) également approuvé dans le cancer prostatique hormonorésistant indolent et se diversifie avec l'utilisation de longs peptides codant pour des mutations en présence d'adjuvants. L'immuno thérapie " adoptive " (transfert aux patients de lymphocytes T spécifi ques de la tumeur) montre aussi son effi cacité dans les essais de phase II contre certaines leucémies, sarcomes et mélanomes. Les virus oncolytiques font une percée en Phase II dans le mélanome et sont à l'étude dans des cancers rares (mésothéliomes, glioblastomes). Ce sont les premières étapes d'une véritable révolution dans la thérapie du cancer, qui aura des répercussions multiples dans d'autres pathologies, y compris inflammatoires et infectieuses.
Intégration de l'analyse de l'immunomodulation induite par les inhibiteurs de mTOR dans leur développement en cancérologie by Laura Mansi( Book )

2 editions published in 2017 in French and held by 2 WorldCat member libraries worldwide

The key role of the mTOR (mammalian Target of Rapamycin) pathway in cellular homeostasis raises a real interest in many therapeutics areas. Inhibitors of mTOR (mTORi) are used for graft rejection prevention to inhibit the T lymphocyte (LT) activation and induce regulatory T cells (LTreg). In cancerology, they are used for their antiproliferative and antiangiogenic actions. However, the clinical efficacy of those treatments is low. Although several mTORi resistance mechanisms linked to the tumor cell have been identified, their impact on the immune system appears as a key factor in their efficiency. Thus, our hypothesis is that the clinical efficacy of mTORi could also be dependent of an anti-tumoral immunity modulation resulting from those treatments.We performed an immunomonitoring of the Treg rate and the tumor specific Th1 anti-tumor response among a prospective cohort of patients with a metastatic renal carcinoma treated by everolimus (mTORi). We observed that the Treg rate and the suppressive function increase after the second month of treatment for almost all the patients. Paradoxically, an increase of the Th1 anti-tumoral response has also been observed for these patients. At disease progression, a majority of the patients has shown an important increase of Treg with a decrease of the Th1 response. Thus, we have been able to define different immune profiles based on the modulation of these two parameters. Progression free survival of patients with an earlier decrease of Treg and an increase of Th1 response was significantly longer compared to other patients (13.2 vs 4 months p=0.02). This immunomodulation has been consistently confirmed with patients affected by neuroendocrine tumor and treated with everolimus. The treatment impact on Treg and the Th1 response was not related to the pharmacokinetic of the drug. Thereafter, we have studied in vivo the impact of mTORi on the anti-tumoral immune response with mice affected by different tumors. We have observed the same increase of Treg in mice treated with mTORi as the increase observed in the patients. Thus, using antibodies depleting the Treg or transgenic mice allowed us to confirm the deleterious role of Treg on the anti-tumor mTORi efficacy. Those results strongly suggest that mTORi have a double effect on the immune system, a harmful impact by the induction of an immunosuppressive environment and a positive impact by the increase of the anti-tumor Th1 response.In a second time, we have studied the positive effect of mTORi on the immune system in order to optimize the anti-tumoral immunotherapies. We have shown that the administration of temsirolimus (mTORi) improves the anti-tumoral efficiency of a therapeutic vaccination on mice. Indeed, the synergic effect of this combination is tied with an augmentation of tumor infiltrate anti-tumor T CD8 with a central memory phenotype. The efficiency of this combination has been greatly improved by the addition of an antagonist CCR4 allowing the elimination of Treg generated by temsirolimus.In conclusion, mTORi remain a promising strategy in cancerology even if their use is likely to be reduced as new immunotherapies such as checkpoint inhibitors (renal carcinoma) or other targeted therapies (cycline dependent kinase inhibitors in breast cancer) appeared. In the future, the development of mTORi must integrate biomarkers taking into account the impact of these treatments on the immune system, and therapeutic combination such as the immunotherapy
Optimisation des vaccins peptidiques anti-cancers à but thérapeutique par l'utilisation d'un vecteur omposé de nanotubes de nitrure de bore et combinaisons avec les anticorps anti-PD-L by Laurie Rangan( )

2 editions published in 2020 in French and held by 2 WorldCat member libraries worldwide

The aims oftherapeutic anti-cancer vaccines are to induce and/or reactivate antitumor T cell responses. It consists of the injection of tumor-associated antigens designed to activate T cells. Nonetheless, these approaches have not reached success so far, with no commercial vaccines available due to the limited efficiency that can be explained by a Jack of immunogenicity and by immunosuppressive mechanisms, involving immune checkpoint pathways. The recent progress in the comprehension ofresistance mechanisms allowed the development of innovative vaccines. In this PhD project, the vaccine efficiency have been investigated through the use ofboron-nitride nanotubes (BNNT) as a vaccine vector, and the use ofblocking antibody targeting the PD-LI, a pathway involved in the inhibition ofT cells. To evaluate these strategies in preclinical mouse mode! using humanized HLA expressing mice, I identified in a first work a transplantable tumor mode! transplantable in these mice. This cell line, coming from a sarcoma naturally occurred in a HLA-A2/DR1 mouse and then named SARC-Ll, triggered a palpable tumor few days after a subcutaneous injection. These tumors are sensitive to chemotherapies and anti-checkpoint immunotherapy (anti-PD-1/PD-Ll) to what is associated an increase of CD8 T cell infiltration. This cell line has been genetically modified to highly express HLA-A2, HLA-DRl molecules and also to express human tumor associated antigen. Overall, the SARC-Ll characteristics allow using it as a relevant preclinical tool for the evaluation of antitumor immunotherapies in human settings.In vitro experiments showed that dendritic ce Ils ( derived from human monocytes, MoDC) were able to intemalize BNNT carrying human telomerase-derived peptides (named UCPs for universal cancer peptide). This did not impact viability (Annexin-V/7AAD) or expression of maturation markers (CD80/CD86/CD83/HLA-DR) on MoDC. However, BNNTUCP treated MoDC induced a telomerase-specific CD4 T cell activation, while any CD8 T cell activation was induced, showing the absence of cross-presentation of UCP in vitro. Immunization of HLA-A2/DRI mice with BNNT-UCP triggered higher anti-UCP CD4 and CD8 T cell responses (4-5 fold increased) than UCP+IFA or carbon nanotubes-UCP (CNT-UCP). The increased immunogenicity ofBNNT-UCP was positively correlated with a delay oftumor growth in SARC-A2 UCP+ tumor-bearing mice, which was associated with an increase of anti-UCP CD8 and CD4 T cells in the tumor microenvironment. The use of an anti-PDLI antibody in combination with an anti-tumor vaccine have been investigated using the broadly used TCI HPV+ tumor mode! on C57BL/6NCrl mice and SARC-A2/DR1 expressing D393-CD20 tumor antigen (Henry et al., 2010). Mice were treated by simultaneous injection of the peptide vaccines and the anti-PD-Ll (conco-combo) or sequential combination with anti-PD-Ll injection started after the last boost vaccine (seq-combo). For the conco-combo treated group, a significant delay oftumor growth and total tumor regression (for 60% ofmice) were observed compared with other treated groups. Sequential combination of anti-PD-Ll abrogated the effect of the vaccine or anti-PD-LI treatment used alone. The synergie effect of the combo-conco group was associated with an increase ofintratumoral CD8 T cells presenting an effector memory profile (CD44+CD62L+) and increased viability (Annexin-V·J7AAD·) compared with other groups. Moreover, a peripheral T cell response specific to another tumor-associated antigen (telomerase) was observed, demonstrating the tumor epitope spreading phenomenon by concomitant treatment
Etude des réponses lymphocitaires T spécifiques de néoantigènes tumoraux après immunomodulations induites par des chimiothérapies by Sindy Vrecko( Book )

2 editions published in 2018 in French and held by 2 WorldCat member libraries worldwide

Immunologie fondamentale et immunopathologie : enseignements thématique et intégré : tissu lymphoïde et sanguin, immunopathologie et immuno-intervention by Collège des Enseignants d'Immunologie( )

1 edition published in 2018 in English and held by 2 WorldCat member libraries worldwide

Rédigé sous l'égide du Collège des Enseignants d'Immunologie (Assim), cet ouvrage présente l'intégralité du programme de L2-L3 en immunologie fondamentale et immunopathologie et constitue le référentiel national.Au terme d'un important travail collectif de concertation pédagogique, les auteurs mettent à disposition des étudiants un manuel complet et synthétique qui s'articule en 2 parties: Tissu lymphoïde et sanguin ; Immunopathologie et immuno-intervention. L'ouvrage tout en couleurs comporte 35 chapitres, dont le contenu clair et didactique est étayé de nombreux tableaux et schémas originaux. A la fin de chaque partie, une série de QCM corrigés permet au lecteur de tester ses connaissances et de s'autoévaluer. Cet ouvrage s'inscrit dans une nouvelle collection dédiée aux UE du programme de L2-L3 : Les cours de L2-L3 médecine, dont le format et la maquette en couleurs offrent une clarté de lecture et facilitent la compréhension et la mémorisation. [Elsevier-Masson]
Identification de nouveaux biomarqueurs des cancers colorectaux by Reyhan Hasanova( )

2 editions published in 2019 in English and held by 2 WorldCat member libraries worldwide

Le cancer colorectal (CCR) est l'un des cancers les plus fréquents au monde avec les cancers du poumon et de la prostate. Une estimation précoce du pronostic pourrait aider à réduire la mortalité de ce cancer et l'implémentation de nouveaux biomarqueurs est devenu indispensable. Dans cette étude nous avons évalué deux molécules pour mieux caractériser et apprécier le pronostic du CCR : l'angiopoiétine-2 (Ang2) et la Mésotheline (Msln). Nous avons d'abord analysé des données transcriptomiques associés à des données de survie et collectés à partir de bases de données publiques. 1617 transcriptomes avaient été produites par des puces ADN et ont été téléchargés de la base GEO (NCBI Gene Expression Omnibus) 573 autres transcriptomes produits par RNAseq ont été extraits de la base de données du TCGA (The Cancer Genome Atlas). Nous avons ensuite réalisé des dosages plasmatiques par méthode ELISA chez 20 donneurs sains et 51 patients atteints de CRC métastatiques suivis dans le cadre d'une étude locale. Les analyses de survie pour Ang2 dans les transcriptomes ont montré qu'une expression intratumoral élevée d'Ang2 était associée à une baisse de la survie globale (OS, "Overall survival") et de la survie sans rechute (RFS, "relapse free survival") y compris chez les patients en stade localisé. Comme attendu, l'expression intratumoral d'Ang2 était associée à l'infiltration stromale et l'angiogenèse mais les analyses multivariées ont montré qu'Ang2 était bien un facteur indépendant de la survie (OS) après ajustement avec toutes les variables disponibles (incluant la classification CMS, "Consensus Molecular Subtypes"). Les dosages plasmatiques d'Ang2 chez les patients atteints de CRC métastatique ont montré que les taux d'Ang2 étaient plus élevés chez les patients que chez les donneurs et qu'un taux élevé était associé à une PFS plus basse. Une expression de Msln élevée dans les transcriptomes était associée à une survie réduite (OS et RFS). C'était également un facteur de risque indépendant de la survie (OS et RFS). L'analyse des voies de signalisations a montré que l'expression de Mésotheline était associée à la voie des éxosomes. Les dosages sériques de Msln ont également montré que les taux sont plus élevés chez les patients que chez les donneurs sains. Enfin, les patients avec des valeurs plus élevées de Msln avaient une survie OS plus basse. Au total, ces résultats suggèrent qu'Ang2 et Msln sont tous deux des biomarqueurs pronostiques pour le CRC. Nous planifions maintenant de stratifier le pronostic en fonction d'une utilisation combinée de ces deux marqueurs
Profil inflammatoire et immunitaire de la BPCO induite par les poussières organiques by Sophia Keddache( )

1 edition published in 2020 in English and held by 2 WorldCat member libraries worldwide

Introduction : la bronchopneumopathie chronique obstructive (BPCO) est caractérisée par une réponse inflammatoire anormale. L'exposition au tabagisme induit une inflammation de type Thl et Thl 7 dans la BPCO. La réponse inflammatoire et immunitaire liée à l'exposition aux particules organiques demeure méconnue.L'objectif de notre étude était de caractériser le profil inflammatoire et immunitaire de la BPCO induite par les poussières organiques. Méthodes : la distribution des cellules T, B et Natural Killers (NK) a été étudiée en cytométrie en flux et les cytokines inflammatoires (IL-l p, IL-6, TNF-Œ), Thl (IFN-Y), Th2 (IL-4, IL-13), et Thl 7 (IL-17), ont été dosées par ELISA à l'état basal et après stimulations (LPS, flagelline, billes de CD3/CD28), dans 3 groupes de sujets : BPCO non tabagiques exposés aux poussières organiques (F-COPD, n=16), BPCO tabagiques exposés aux poussières organiques (FT-COPD, n=7), des BPCO tabagiques non exposés aux poussières organiques (T-COPD, n=21), et comparés à 12 sujets contrôles.Résultats : le groupe F-COPD présentait un taux de cellules NK inférieur aux autres groupes (p=0,03), et une répartition des sous-populations lymphocytaires T différents par rapport au groupe contrôle(p<0,05). A l'état basal, les sujets BPCO présentaient un taux plus élevé de cytokines inflammatoires. Les taux de TNF-ct étaient significativement plus élevés chez les tabagiques que les contrôles. Après stimulation non spécifique, l'IL-1ß ainsi que l'IL-17 étaient significativement plus élevées chez les BPCO. La flagelline induisait des taux d'IL-13 significativement plus bas dans le groupe T-COPD par rapport aux F-COPD et aux contrôles (p<0,05). Conclusion : la BPCO liée aux poussières organiques induit des réponses inflammatoires différentes de celles de la BPCO dite tabagique avec une polarisation de type Thl 7/Th2
Identification de nouveaux transcrits alternatifs du gène CD20 humain, différentiellement exprimés dans les hémopathies impliquant le lymphocyte B by Clémentine Gamonet( Book )

2 editions published in 2015 in French and held by 2 WorldCat member libraries worldwide

D393-CD20 is a protein encoded by an alternatively spliced transcript of human cd20 gene, expressed only on tumoralB lymphocyte (Henry et al, Blood2010). Based on this results, we decided to study the cd20 splicing in pathologies involving B cells. During this work, we identified 5 cd20 alternative transcripts, among them the D393-CD20 variant. The 4 others werenamed according to their size: D657-, D618-, D480- and D177-CD20.D657- and D618-CD20 are weakly expressed in healthy donor and overexpressed in pathologies involving Blymphocytes, whereas D393-CD20 is only expressed in B malignancies. Splicing pattern of patients suffering from pathologies involving B lymphocyte (cancers, auto-immune diseases, EBVinfection) were performed by quantitative PCR, and these patterns revealed a splicing deregulation in these pathologieswith a higher proportion of alternative variants compared with healthy dormors. The observation of a specifie expression of D393-CD20 in tumoral cells suggests a splicing deregulation associatedwith oncogenesis, particularly in lymphoma derived from germinal center. If in our in vitro models, no direct correlation between D393-CD20 expression and resistances to anti-CD20 antibodiestreatments hâve been observed, when shown that these antibodies induced cd20 splicing modulation. These results open the way to a deeper study to determine the interest ofcd20 splicing deregulation as a biomarker, andthe impact of theses deregulations on CD20 protein expression since these protein is a preponderant target of therapeuticstrategies used in pathologies involving B cells
Identification de peptides immunogènes dérivés de la télomérase et optimisation de l'utilisation de la sous-unité B de la toxine de Shiga comme vecteur vaccinal by Olivier Adotevi( Book )

1 edition published in 2007 in French and held by 2 WorldCat member libraries worldwide

Impact des inhibiteurs de la voie mTOR sur la réponse immunitaire T anti-tumorale by Laurent Beziaud( Book )

2 editions published in 2015 in French and held by 2 WorldCat member libraries worldwide

The mammalian Target of Rapamycin (mTOR) pathway plays a central role in the regulation of cell growth andmetabolism, and is involved in oncogenesis. Everolimus and temsirolimus are two mTOR inhibitors (mTORi) approvedfor renal and breast carcinoma treatments. However, accumulating evidence highlights a central role for mTOR pathwayin T cell immunity. We showed that 21 out of 23 metastatic renal cell carcinoma patients under everolimus treatmenthad an increase of Tregs atter everolimus treatment. Paradoxically, strong antitumor Th 1 responses were detected andthen greatly decreased at the time of disease progression when high expansion of Tregs occurred. Furthermore, weidentified three immune groups based on the early modulation of both Treg and anti-tumor Thl cells and found thatpatients with {low Tregs plus high anti-tumor Thl cells} showed the best survival. In vitro, mTORi-exposed Tregs highlysuppressed T cell proliferation and Thl-associated cytokines production. We showed in vivo that T cells depletiondifferentially modulated the antitumor efficacy of mTORi. Although anti-mTOR effect was loss in B16-OVA-bearingmice lacking CD8 T cells, CD4 T depletion increased mTORi efficacy. The studies conducted in mice demonstratedthat the presence of Tregs in vivo altered the responses to mTORi via a mechanism involving the inhibition of antitumorCD8 T cell responses. Finally the efficacy of mTORi was improved by combination with Tregs depleting agents andvaccines. Altogether, our results describe for the first time a dual impact of host adaptive antitumor T cell immunity onthe clinical effectiveness of mTQRi and prompt their association with immunotherapies
Etude de la réponse T CD4 anti-télomérase périphérique dans les cancers : méthodes d'analyse et intérêt pour le monitoring en immuno-oncologie by Caroline Laheurte( )

2 editions published in 2020 in French and held by 2 WorldCat member libraries worldwide

The concept of cancer immunity cycle supports the presence of pre-existing antitumor T cells in cancer patients that are controlled by multiple activation/inhibitory signais. Although many studies have heavily focused on CD8 T cells responses, evidences also support the critical antitumor role of CD4 T cell immunity in the tumor microenvironment. However, the role of systemic tumor-specific CD4 Thl responses has not been widely explored. ln this thesis project, we investigated immunological characteristics and clinical relevance of circulating antitumor CD4 Thl response in a cohort of 170 non-small-cell lung cancer (NSCLC} patients (TeloCapl study). The antitumor CD4 Thl response was assessed by IFN-y ELISPOT assay in blood lymphocytes using a mixture of highly promiscuous HLA class II-restricted epitopes from telomerase (TERT). The presence of anti-TERT Thl response was detected in 59/170 patients (35%). We showed that circulating TERT-specific CD4 T cells detected in NSCLC produce IFN-y, TNF-a, and IL-2, and expressed CXCR3, underlining a Thl polarization. The frequency of anti-TERT Thl response gradually decreased from localized to metastatic NSCLC stage, 55% versus 24% respectively. We found that NSCLC patients who exhibited high rates of anti-TERT Thl cells had better overall survival compared with patients with anti-TERT Thllow in blood (not reached versus 12 months, P = 0.009). Notably, an opposite link was found between antiTERT Thl and exhausted T cells co-expressing PD-1+ and TIM-3+, so that that the presence of anti-TERT Thl response in patients was associated with lower rates of exhausted PD-1+/TIM-3+ T cells in blood. Based on the levels of anti-TERT Thl and PD-1+/TIM-3+ CD4 T cells in blood, we stratified NSCLC patients into three distinct prognostic groups (best, intermediate and poor). The best group represents patients with anti-TERT Thlhigh/ exhausted CD4Iow supporting a protective antitumor rote of systemic anti-TERT Thl response in NSCLC. By searching factors likely to influence the circulating anti-TERT Thl response, we described an immune regulatory role of the proangiogenic factor as angiopoietin-2 (ANGPT2). We found in this cohort of NSCLC that the presence of an ANGPT2 rich environment was strongly associated with an impairment of pre-existing anti-TERT Thl responses. We demonstrated that TIE2, the receptor for ANGPT2 was overexpressed on subsets of monocytic Myeloid-derived suppressor cells (MMDSC) and showed a positive correlation between the level of ANGPT2 and circulating rate of TIE2+M-MDSC. The presence of an ANGPT2/ TIE2+ MMDSC rich signature in blood was associated with an impairment of anti-TERT Thl response. We demonstrated that ANGPT2 sensitizes TIE2+ M-MDSCs cells to suppress antitumor T cells. Consequently, upregulation of the ANGPT2/TIE2+M-MDSC signature in blood was associated with a poor prognosis in NSCLC. Thus, we identify the ANGPT2/TIE2+ M-MDSC axis as a participant in tumor immune evasion. Collectively, our results reported the natural history of the systemic anti-TERT CD4 Thl immunity in NSCLC and showed its opposite role against T cell exhaustion and angiogenesis. These results support the interest ta use the anti-TERT Thl response as a new blood-based tool for patients' stratification and for therapy decision
Metronomic cyclophosphamide therapy in hormone-naive patients with non-metastatic biochemical recurrent prostate cancer: a phase II trial by Fabien Calcagno( )

1 edition published in 2016 in English and held by 2 WorldCat member libraries worldwide

Etude des réponses lymphocytaires T CD4 anti-tumorales : de l'identification de cibles à leur utilisation pour l'immunomonitorage by Jeanne Galaine( )

3 editions published in 2015 in French and held by 2 WorldCat member libraries worldwide

Les cellules du système immunitaire sont capables de reconnaître et d'éliminer les cellules cancéreuses prévenant ainsi l'apparition de cancers. Parmi celles-ci, l'activité antitumorale est principalement attribuée aux lymphocytes T CD4 helper de type 1 (Thl). Les lymphocytes CD4 sont activés lors de la reconnaissance d'un antigène (Ag) de tumeur présenté par le complexe majeur d'histocompatibilité de classe II (CMH-II). Ils possèdent des propriétés cytotoxiques propres et activent les autres cellules immunitaires. Dans un premier temps, nous nous somme intéressés au mécanisme de présentation sur le CMH-II de la télomérase (hTERT). La protéine hTERT est capable d'interagir avec les HSPGs facilitant ainsi son internalisation par les DC. Elle emprunte ensuite les voies endolysosomale et cytosolique pour générer des peptides nommés UCP présentés dans le contexte HLA-DR. Cette découverte soutient son utilisation en immunothérapie associée aux chimiothérapies. Nous avons ensuite identifié quatre peptides dérivés de hTERT restreints HLA-DP4 puis comparé leur immunogénicité avec les UCP. Cette analyse a mis en évidence la supériorité des UCP en termes d'immunoprévalence et d'immunodominance. Enfin, nous avons étudié l'impact de l'acquisition d'une résistance à l'oxaliplatine sur le profil antigénique de lignées tumorales de cancers colorectaux (CCR). L'évaluation des réponses immunitaires de patients atteints de CCR nous a permis d'identifier des peptides immunogènes dérivés d'Ag surexprimés après une exposition à l'oxaliplatine. En conclusion, ces travaux pourront participer à l'amélioration des stratégies d'immunothérapie et d'immunomonitoring ciblant les lymphocytes CD4 Thl
Caractérisation des réponses immunitaires périphériques des cancers épithéliaux exprimant les papillomavirus humains by Laurie Spehner( )

2 editions published between 2019 and 2021 in French and held by 2 WorldCat member libraries worldwide

The increased incidence and the lack of therapeutic resources for non-operable forms of HPV+ cancer patients constitutes a major challenge. High immunosurveillance in HPV-associated tumors and the presence of viral antigens associated with oncogenesis of these cancers should focus on the development of immunotherapy strategies such as anti-tumor vaccination and adoptive transfer of TILs. These technological advances encourage a better understanding of immune responses in these pathologies and aim to develop strategies combining immunotherapies for the treatment of all HPV-related cancers. We first looked for tumor antigens associated with the prognosis of patients with anal canal cancer. The patients were treated with a combination of chemotherapy whose therapeutic benefit was demonstrated by our team. Monitoring specific T-immune responses in the peripheral blood of these patients has shown that telomerase is a tumor antigen associated with SCCA; and moreover that the presence of Telomerase-specific LT Th1 is a predictor of progression-free survival at 12 months. Our data also highlighted the influence of M-MDSC on the T-specific immune responses of our antigens as well as on the survival of patients with SCCA. As a result, M-MDSCs are a prognostic factor in the response to treatment of patients with metastatic SCCA treated with chemotherapy. The second work of this thesis validated the feasibility of isolating TILs from biopsy samples from patients with HPV-associated cancer. The specific T immune responses of HPV16 oncoproteins are correlated in 50 and 60% of cases between peripheral blood and tumor. The final objective of this thesis work demonstrated the immunogenicity of the SALL4 protein, a transcription factor associated with pluripotency and self-renewal of embryonic stem cells. We have generated anti-SALL4 CD4 Th1 response analysis technology to monitor immune responses in patients with digestive adenocarcinoma. Our work has also shown a low frequency of SALL4-specific T responses in the peripheral blood of patients with SCCA. These results suggest that the presence of specific SALL4 responses in the peripheral blood of SCCA patients could be subject to immunomonitoring resulting in a decrease in the frequency of CD4 LT SALL4+. It would be interesting to analyze the presence of specific LT of this antigen in the early forms of HPV-related cancers
Marqueurs de réponse thérapeutique du mélanome by Charlée Nardin( )

1 edition published in 2021 in French and held by 1 WorldCat member library worldwide

Introduction: The prognosis of patients with advanced melanoma has been revolutionized by the introduction of targeted therapies and immune checkpoint inhibitors (ICI). However, less than 50% of patients respond to anti-PD1 monotherapy. Predictive markers of response and resistance to ICI are a broad field of research due to its medico-economic impact. Predictive markers will allow the selection of patients who may benefit from ICI without toxicities.Methods: We investigated three markers of therapeutic response in melanoma: vitiligo, telomerase-specific CD4 T-cell immunity and expression of PD-L1 in circulating exosomes in melanoma patients.Results: First, taking into account the lead-time bias, we demonstrated that vitiligo onset was associated with increased survival in patients with advanced melanoma treated with anti-PD1. Furthermore, repigmentation may be a sign of disease progression. Second, we evaluated circulating CD4 T helper type 1 (Th1) response against telomerase (anti-TERT Th1 response) in patients with melanoma. Anti-TERT Th1 response was less frequent in melanoma patients with a Breslow index superior to 1 mm and AJCC >=II. Furthermore, anti-TERT Th1 response was predictive of response to ICI and associated with a better prognosis in patients treated with ICI only. Third, we evaluated the expression of PD-L1 in circulating exosomes (exo-PD-L1) from melanoma patients. Changes in exo-PD-L1 were correlated with disease evolution. Increased of exo-PD-L1 >100pg/ml was associated with disease progression and allowed us to stratify the population into 2 groups with different prognosis. Discussion: Treatment strategy need to be personalised and will be tailored with prognostic markers such as biomarkers. Vitiligo, anti-TERT Th1 response and exo-PD-L1 associated with others may be prognostic markers, which may help in clinical practice to chose and tailor the treatment strategy of melanoma patients
Etude phénotypique et fonctionnelle des cellules NK dans un contexte de cancer et d'inflammation by Émilie Picard( Book )

1 edition published in 2017 in French and held by 1 WorldCat member library worldwide

NK cells are innate lymphocytes involved in the recognition and elimination of infected or tumor cells. Their cytotoxic activity is finely regulated by a set of activating and inhibitory receptors. However, receptors expression and NK cell functions may be modified according to environment. Here, we were interested in NK cell-phenotype and function modulations and their relationship with CD4 T cells, in NSCLC patients and under IL-21 influence in inflammatory context. The first study highlighted an increase circulating rate of CD56dim CD16- NK cell subset concomitantly with a decrease rate of CD56dim CD16+ NK cell subset in NSCLC patients. Ex vivo analysis of NK cell phenotype highlighted a specific group of patients with an overall altered expression of NCRs and NKG2D on NK cell subsets. The main defect was the decrease of NK cells expressing NKp46 and we showed a negative correlation between the patients' survival and NKp46+ NK cell percentage. Interestingly, NKp46 neutralization on NK cells was associated with a better antitumor CD4 T cell response. The second study showed that IL-21 promotes the differentiation of a specific NK cell subset coexpressing CD86/HLA-DR and CD86/CD30. While NK cell activation via CD30 promotes a high degranulation and IFN-[gamma] secretion, IL-21-activated NK cells also produce MIF. This soluble factor provide costimulatory signaling during naïve CD4 T cell priming inducing the differentiation of uncommitted central memory T cells. Such HLA-DR+ MIF+ NK cells were identified in inflammatory human appendix suggesting that they could activate CD4 T cells in vivo. Altogether, these studies highlighted a different modulation of NK cell phenotype accordingg to envoronment which could impact the crossstalk NK-T celles. thus, these findings support a regulatory role of NK celles in adaptive immune responses
Anti-CTLA-4 antibody / CTLA-4 molecule immuno-modulator mechanisms and its consequences on the reinforcement of anti-melanoma immune responses by Joana Melo Félix( )

1 edition published in 2016 in English and held by 1 WorldCat member library worldwide

Melanoma is a skin cancer with incidence increasing at dramatic rates worldwide. Ipilimumab, an anti-CTLA-4 therapy developed in the view of counter-balancing the inhibitory role of CTLA-4 in T lymphocytes, was the first immune checkpoint inhibitor demonstrating to extend overall survival in patients with metastatic melanoma, with FDA approval in 2011. However, biomarkers allowing the identification of the subset of patients that will more likely benefit from this immunotherapy or that may allow a good monitoring of patient clinical management during treatment are lacking. The principal objective of this work was to identify potential and early predictive biomarkers of ipilimumab response and/or survival in a cohort of 77 metastatic melanoma patients. Firstly, serum levels of melanoma markers such as LDH, S100B and soluble MICA (and its counter-part anti-MICA antibody), tumour markers associated with tumour development and/or immune escape, were assessed. A correlation between lower baseline levels of LDH and S100B, sustained after the first and second doses of ipilimumab, and treatment response and survival was observed, suggesting their potential utility in treatment monitoring. In addition, higher baseline levels of soluble MICA were found to be associated with a less frequency of immune-related adverse events, which might provide important information for the management of frequent ipilimumab-related adverse events. Secondly, immune markers with a special focus on transcription factors, cytokine secretion and chemokine receptors of T lymphocytes and memory T subsets were assessed. An association between baseline absolute lymphocyte counts and extended overall survival as well as better treatment response was found. In addition, a global effect of ipilimumab on the expansion of conventional memory T cells was observed, which was associated with treatment response. By contrast, frequencies of the recently described stem-cell memory T cells were shown to decrease despite increased proliferation, suggesting a process of differentiation. Additionally, ipilimumab induced the expansion of CXCR3, CCR4 and CCR6-expressing T lymphocytes and effector cytokines secretion capacity. Early increased levels of Eomes-expressing CD8+ T cells were found to be associated with disease control. Lastly, and based on the previous results, we investigated the ability of patients' memory T cells to proliferate under in vitro stimulation. We found that, in contrast to healthy subjects, patients possess a defect in the ability of stem-cell memory T cells expansion in vitro, that might be related to a defect in Eomes and Ki-67 regulation
Phenotypic and Functional Characteristics of Natural Killer (NK) Cells from Metastic Melanoma Patients by Meriem Messaoudene( )

1 edition published in 2015 in English and held by 1 WorldCat member library worldwide

Cytotoxic immune effectors can control the development and growth of certain solid tumours. Among these cytotoxic effectors, NK cells are capable of rapidly eliminating tumour cells and virus-infected cells without prior immunization.The objectives of my thesis were to evaluate the potential role of NK cells in the immune response against melanoma. First, I have characterized the functional status of blood NK cells from melanoma patients at different stages of the disease. I showed that ex vivo NK cells from most advanced stage III-IV patients display low lytic potential. However, IL-2-activated NK cells from patients efficiently lyse melanoma cells and that independently to the clinical stage. Moreover, the expression of the activating receptor NKp46/NCR1 by blood NK cells was decreased in stage IV patients compared to healthy donors, and a positive correlation between NKp46 expression by NK cells and the duration of stage IV was found. I have also characterized ex vivo NK cells infiltrating metastatic lymph nodes (M-LN) from stage III melanoma patients. I have identified in M-LN a unique subpopulation of mature CD56brightCD16+ NK cells that expressed higher NCR, NKG2D, KIRs, and perforin levels than CD56brightCD16- NK cells counterpart. NK cells from M-LN activated with IL-2 or IL-15, rapidly lysed metastatic melanoma cell lines with higher efficiency than autologous blood NK cells. Finally, to determine if NK cells display a prognostic value, I analysed by immunohistochemistry NK cells and other immune cells infiltrating positive and negative sentinel lymph nodes (SLN). SLN are characterized by high densities of macrophages and endothelial cells, even higher in SLN+. Few NK cells and Granzyme B+ cells infiltrate SLNs while CD8+ T cells are numerous. Moreover, numbers of NK cells in SLN correlated with higher rate of 5 year-relapse of patients. Compared to SLN, primary cutaneous melanomas contain high numbers of NK cells that are preferentially localized in the periphery of the tumour and are not related to the Breslow. My findings showed that in melanoma patients, circulating and tumour infiltrating NK cells display unique phenotypic and functional characteristics, indicating that tumour may alter their function. However, they respond to cytokine activation and acquire antitumor lytic potential. In the new landscape of melanoma treatment, NK cells are worthy to be considered for combined treatment with BRAF inhibitors
Analyse du microenvironnement et de l'oncogenèse des cancers colorectaux surexprimant l'Angiopoiétine 2 by Marine Jary( )

2 editions published in 2019 in French and held by 1 WorldCat member library worldwide

Colorectal cancer (CRC) is a severe and frequent disease, with important survival improvement due to therapeutic new approaches and surgical methods, even in metastatic setting. It is an heterogeneous entity, and personalized strategies are mandated, whereas few predictive and prognostic biomarkers are available in practical care. Molecular classifications are useful to better understand CRC biological characteristics, but they do not have predictive values, and seem to be inadequate for metastatic setting. Seric biomarkers are attractive since they could recapitulate tumor features, while being simpler and less expansive. There is a need to investigate surrogacy biomarkers illustrating intra tumoral microenvironment, in order to adapt treatment strategies.This thesis is about the clinical and molecular characterization of Angiopoietin 2 (ANGPT2) associated colorectal cancer. Assessment of microenvironment and peripheral immune Th1 response are performed and correlated with this entity.Prognostic value of ANGPT2 in metastatic colorectal cancer was studied in the first part of the manuscript. We described that ANGPT2 plasmatic levels were associated with a worst overall survival in metastatic setting. In the second part, using the open source transcriptomic tools, we decided to define the specific molecular signaling pathways correlated to ANGPT2 expression in CRC and its prognostic value in localized CRC. A specific signature was drawn, combining genes associated with stroma, invasion, angiogenesis, and chemo-resistance. Looking for associated secreted proteins, we could identify a seric signature (combining STC1, CD138 and ANGPT2), predictive for chemo-resistance. An negative correlation was observed between ANGPT2 signature and immune response. The last part of the thesis then explored the prognostic value of anti TERT peripheral immune Th1 response in metastatic colorectal cancer (Epitopes-CRC02 study), and validated its beneficial role for predicting OS. A negative correlation was confirmed, in seric measurement between CD4 immune response and ANGPT2.This work paves the way for individualized treatments in tumors harboring ANGPT2 associated characteristics', targeting the stromal and immune microenvironment. This immune and stromal biomonitoring is feasible and have to be associated to futures clinical studies. Future prognostic scores should probably assess the place of these biomarkers in order to improve their discriminant values
La résolution de l'inflammation comme approche thérapeutique innovante contre le cancer by Audrey Wetzel( )

1 edition published in 2021 in French and held by 1 WorldCat member library worldwide

 
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Immunothérapie des cancers au troisième millénaire
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