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1
Rosenthal, Rachel Suzanne. "Immune editing and surveillance in cancer evolution". Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10047362/.
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Cancer is an evolutionary disease, reliant on genetic diversity and sculpted by selective forces from the immune microenvironment. Here, I use genomics data to decipher the tumor’s evolutionary trajectory and corresponding shifts in the immune contexture to elucidate the events governing tumor immunogenicity and the immune evasive mechanisms evolved by the tumor. To better understand the mutational processes contributing to intratumor heterogeneity in individual tumors, a method to quantify the activity of mutational processes in a single tumor sample was developed and applied to temporally dissected mutations. The clinical relevance of intratumor heterogeneity was examined in the context of immune recognition and modulation. Increased clonal neoantigen burden and minimal neoantigen intratumor heterogeneity were found to associate with improved patient outcome, both in the treatment-naïve and immunotherapy-treated setting. The identification of T-cells recognizing clonal neoantigens further supported the clinical importance of targeting neoantigens present in every cancer cell. Mechanisms of immune evasion were considered through the development of a method to identify loss-of-heterozygosity at the HLA locus, overcoming the challenges posed by the polymorphic nature of the locus. HLA loss-of-heterozygosity was found to be a frequent subclonal event in NSCLC, under strong selective pressure and associated with increased subclonal neoantigen burden. Finally, the immune microenvironment was examined through multi-region RNAseq, permitting the quantification of immune infiltration and allowing for the identification of heterogeneously immune infiltrated tumors. Supporting the interplay between genetic events and the immune contexture, a relationship between the genomic features of the tumor and immune infiltration was observed, with HLA loss-of-heterozygosity specifically identified as occurring within a highly active immune microenvironment. This thesis shows how an improved understanding of the relationship between the tumor and the immune system can illuminate features dictating immune recognition and evasion and how that knowledge may inform the development and implementation of successful immunotherapy.
2
SCHEIDECKER, CATHERINE. "Cellule nk : surveillance immune et resistance naturelle". Strasbourg 1, 1987. http://www.theses.fr/1987STR10724.
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Marri, Eswari. "Immune surveillance of activated immune and tumour cells by surfactant protein D". Thesis, Brunel University, 2015. http://bura.brunel.ac.uk/handle/2438/13847.
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Surfactant protein D (SP-D) is a carbohydrate/charged pattern recognition molecule of the innate immune system. By virtue of its ability to recognize an array of carbohydrate patterns on the surface of a range of pathogens, SP-D can bring about opsonisation, enhanced phagocytosis and killing of a diverse range of viruses, bacteria and fungi. In addition to antimicrobial functions, which also includes bacteriostatic and fungistatic properties SP-D has also been shown to bind allergens derived from a number of sources including house dust mite, Aspergilllus fumigatus and pollen grains. SP-D allergen interaction leads to inhibition of specific IgE binding and subsequent downregulation of histamine release from sensitized basophils and mast cells. Thus, a number of murine models of pulmonary hypersensitivity and allergic asthma induced by ovalbumin, house dust mite and Aspergillus fumigatus allergens/antigens have been tested for the ability of SP-D to dampen allergic symptoms on the immunological parameters. In general, treatment of allergic models with a recombinant fragment of human SP-D (rh SP-D; composed of trimeric, neck and carbohydrate recognition domain) has been shown to cause downregualtion of specific IgE synthesis, pulmonary and peripheral eosinophilia and airway hyper reactivity, and Th2→Th1 polarisation. However, therapeutic alleviation of eosinophilia by rh SP-D treatment became evident when SP-D gene deficient mice were found to be hypereosinophilic In fact, rhSP-D binds well to eosinophils derived from allergic patients and induces apoptosis without affecting eosinophils derived from healthy individuals or non-activated/non-sensitized eosinophils. Proteomic analysis of rh SP-D treated eosinophillic cell line that revealed that apoptosis induction takes place via p53 pathway. In this thesis, proteomic signatures were replicated using a leukemic cell line AML14.3D10 via qPCR analysis by identifying targets from a spectrum of genes, which were either upregulated or downregulated. It appears that in spite of induction of apoptosis by rh SP-D, different cells respond differentially at molecular levels (Chapter 3). Sensing that SP-D can induce apoptosis in altered or transformed cells; the effect of SP-D gene expression within pancreatic cancer cells was also investigated. The experiments confirmed p53 pathway dependence for suppression of cancer. Interestingly, factors responsible for metastasis for cancer are also downregulated by endogenous overexpression of SP-D, as validated by wound healing assay. We conclude that SP-D is a general immunosurveillance molecule, which is involved in the clearance of altered and transformed cells (Chapter 4). Chapter 5 shows a direct interaction between DC-SIGN and rh SP-D that inhibits DC-SIGN interaction of allergens and HIV-1, tow common ligands for SP-D and DC-SIGN. Using transfected human embryonic kidney (HEK) cells expressing surface DC-SIGN, we found that pre-treatment of these cells with rhSP-D suppressed DC-SIGN mediated transmission of HIV-1to co-cultured PBMCs. The effect of rhSP-D-DC-SIGN In conclusion, this thesis highlights a broader immune role of SP-D in homeostasis and probably assigns potential functions of extrapulmonary and/or locally synthesized SP-D within non-lung tissues and blood.
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Kaur, Anuvinder. "Innate immune surveillance in ovarian and pancreatic cancer". Thesis, Brunel University, 2017. http://bura.brunel.ac.uk/handle/2438/15847.
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Activation of innate immune surveillance mechanisms during the development of cancer is well-documented. However, knowledge of how these innate immune proteins, when added exogenously, independent of tumour microenvironment, affect tumour cells is limited. In Chapter 3, the effects of human C1q and its individual globular domains (ghA, ghB and ghC) on an ovarian cancer cell line, SKOV3, have been examined. C1q and globular head modules induced apoptosis in approximately 55% of cells, which involved upregulation of TNF-α and Fas and activation of the caspase cascade. This occurred in parallel to the downregulation of mTOR, RICTOR and RAPTOR survival pathways, which are often over-expressed in the majority of the cancers. Thus, this study provided evidence for another complement-independent role of C1q. The second part of this thesis was to investigate the effect of Human Surfactant Protein-D (SP-D), which is known to modulate secretion of a range of cytokines and chemokines by effector immune cells, such as TNF-a and TGF-β, at mucosal surfaces during infection and inflammation. Our hypothesis was that SP-D can influence these soluble factors as a part of its putative role in the immune surveillance against pancreatic cancer, where the inflammatory tumour microenvironment contributes to the epithelial-to-mesenchymal transition (EMT) invasion and metastases. In this study, a recombinant fragment of human SP-D (rfhSP-D) inhibited TGF-β expression in a range of pancreatic cancer cell lines, thereby reducing their invasive potential by downregulating Smad2/3 expression that may have interrupted signal transduction negatively, which affected the transcription of key mesenchymal genes such as Vimentin, Zeb1 and Snail. Furthermore, prolonged treatment with rfhSP-D induced apoptosis in the pancreatic cancer cell lines via activation of the caspase cascade. Thus, this study added another layer to the well-known protective role of SP-D.
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Cheung, Ann F. "Investigating immune surveillance, tolerance, and therapy in cancer". Thesis, Massachusetts Institute of Technology, 2009. http://hdl.handle.net/1721.1/46809.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2009.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Vita.
Includes bibliographical references.
Maximizing the potential of cancer immunotherapy requires model systems that closely recapitulate human disease to study T cell responses to tumor antigens and to test immune therapeutic strategies. Current model systems largely relied on chemically-induced and spontaneous tumors in immunodeficient mice or on transplanted tumors. Such systems are limited because they fail to reproduce the complex interactions that exist among an emerging tumor, its microenvironment and the multiple elements of an intact immune system. We created a new system that is compatible with Cre-loxP-regulatable mouse cancer models in which the defined antigen SIY is specifically over-expressed in tumors, mimicking clinically-relevant tumor-associated antigens. To demonstrate the utility of this system, we characterized SIYreactive T cells in the context of lung adenocarcinoma, revealing multiple levels of antigenspecific T cell tolerance that serve to limit an effective anti-tumor response. Thymic deletion reduced the number of SIY-reactive T cells present in the animals. When potentially self-reactive T cells in the periphery were activated, they were efficiently eliminated. Inhibition of apoptosis resulted in more persistent self-reactive T cells, but these cells became anergic to antigen stimulation. Finally, in the presence of tumors over- expressing SIY, SIY-specific T cells required a higher level of costimulation to achieve functional activation.
(cont.) Adoptive cell transfer (ACT) therapy for cancer has demonstrated tremendous efficacy in clinical trials, particularly for the treatment of metastatic melanoma. There is great potential in broadening the application of ACT to treat other cancer types, but the threat of severe autoimmunity may limit its use. Studies in other model systems have demonstrated successful induction of anti-tumor immunity against self-antigens without detrimental autoimmunity. This is possibly due to the preferential recognition of tumor over normal somatic tissue by activated T cells. In our system, SIY provides a means to achieve this bias because of its over-expression in tumors. Thus, we applied adoptive T cell transfer therapy combined with lymphodepleting preconditioning to treat autochthonous lung tumors over-expressing SIY self-antigen. With this treatment, we overcame peripheral tolerance, successfully inducing large number of functional anti-tumor T cells. These T cells are able to influence lung tumors over-expressing self-antigen. Importantly, despite large numbers of potentially self-reactive T cells, we did not observed overt autoimmunity. Immune tolerance thwarts efforts to utilize immune therapy against cancer. We have discerned many mechanisms by which tolerance to cancer in potential achieved. Both Foxp3+ T regulatory cell and myeloid-derived suppressor cell populations are expanded in the presence of cancer in our mouse models.
(cont.) In addition, we identified LAG-3 as a potential factor that serves to limit anti-tumor T cell activity in the context of adoptive cell transfer therapy. Our new system represents a valuable tool in which to explore the mechanisms that contribute to T cell tolerance to cancer and to evaluate therapies aimed at overcoming this tolerance. In addition, our model provides a platform, on which more advanced mouse models of human cancer can be generated for cancer immunology.
by Ann F. Cheung.
Ph.D.
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Loughhead, Scott McNabb. "Immune Surveillance by Effector and Memory CD8+ T Cells". Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:26718721.
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During priming, CD8+ T cells integrate a plethora of signals that affect their differentiation into subsets of CD8+ T cells with distinct migratory properties and functions. Given that CD8+ T cells exert their protective function via cell-cell contacts, the migratory patterns and spatial distribution of CD8+ T cell subsets induced by primary challenge are of critical importance to the host. Dendritic cells (DCs), as the primary initiators of these responses, play a pivotal role in shaping the size and differentiation status of CD8+ T cells that emerge. However, inadequate markers for CD8+ T cell subsets have hindered study of their lineage relationships, as well as their migratory behaviors. Here, we use a novel marker for identification of CD8+ T cell subsets to interrogate whether subsets of DCs skew CD8+ T cell fate decisions, the differentiation pattern of CD8+ T cell subsets, and the migratory behavior of these CD8+ T cell subsets.
Within secondary lymphoid organs (SLOs), CD8+ T cells encounter subsets of DCs that may differentially impact subsequent T cell fate decisions. While distinct DC subsets were found to influence CD8+ T cell priming and subsequent differentiation in vitro, these differences were masked when priming occurred in vivo. This prompted us to delve deeper into how CD8+ T cell subsets are defined in vivo. Classically, memory CD8+ T cells are divided into two subsets: central memory T cells (TCM) and effector memory T cells (TEM). Based on the variable expression of the chemokine receptor, CX3CR1, we define TCM as CX3CR1- and TEM as CX3CR1high. Additionally, a previously undefined subset of T cells was identified that express intermediate levels of CX3CR1. Flow cytometric analysis of the subsets migrating through murine peripheral tissues in the memory phase established CX3CR1int cells as the dominant subset, thus these cells have been termed peripheral memory T cells (TPM). Lineage tracing of these three subsets established a uni-directional relationship where increasing levels of CX3CR1 marked further terminal differentiation: TCM (CX3CR1-) to TPM (CX3CR1int) to TEM (CX3CR1hi).
The finding that TPM, and not TEM, migrated through peripheral tissues was intriguing because it contradicted previous studies suggesting that TEM had this migratory pattern. To resolve this contradiction, we visualized the migration of TEM precursors, CX3CR1hi effector T cells (TEff), by intravital multi-photon microscopy (IV-MPM) in real-time. Surprisingly, CX3CR1hi TEff adhered to and patrolled along the dermal endothelium of mice. Specifically, migration was enriched along arteriolar endothelium and tended to be against blood flow. Patrolling occurred for both CX3CR1hi TEff and TEM and was limited to CX3CR1hi CD8+ T cells and CX3CR1hi monocytes, but was not dependent on functional CX3CR1. Moreover, addition of cognate antigen (Ag) resulted in rapid stopping of Ag-specific T cells, suggesting that patrolling T cells scan arteriolar endothelium for cognate Ag. Together, these results challenge the paradigm that TEM function by migration through peripheral tissues and establish a new migratory behavior by TEM and their effector precursors that promotes intravascular scanning of arteriolar endothelium.Medical Sciences
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Sowinski, Stefanie. "Transmission and immune surveillance of human T cell-tropic retroviridae". Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501764.
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Textor, Johannes [Verfasser]. "Search and learning in the immune system : models of immune surveillance and negative selection / Johannes Textor". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2012. http://d-nb.info/1024336921/34.
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Blaimer, Stephanie [Verfasser] y Edward K. [Akademischer Betreuer] Geissler. "Impact of innate and adaptive immune cells in tumor immune surveillance / Stephanie Blaimer ; Betreuer: Edward K. Geissler". Regensburg : Universitätsbibliothek Regensburg, 2020. http://d-nb.info/1210729202/34.
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Strickland, Ian. "The role of immune surveillance in inflammatory reactions in human skin". Thesis, University of Liverpool, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307670.
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Joyce, Stephen Paul. "Exploring the role of Vδ1+ γδ T cells in immune stress surveillance". Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/5904/.
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γδ T cells play a central role in the detection of epithelial stress as a component of the lymphoid stress surveillance response. Despite their implication in a range of conditions, including several cancers, little is known about how they interact with their antigenic targets, particularly the interaction of γδ TCRs with their ligands. In this thesis I used molecular and structural modelling techniques to characterise recognition of an epithelial stress ligand, EphA2, by a Vδ1+ γδ T cell, MAU. This resulted in a tripartite model of recognition, involving coordinated interaction of EphA2 with both the TCR and its cognate A-ephrin ligands on the T cell, and the identification of a surface patch on the ligand binding domain of EphA2 that potentially represents a TCR binding site. I also performed sequence-level TCR repertoire analysis to assess γδ T cell populations in human colon and liver, and explored, the effect of chronic cytomegalovirus infection on the Vδ1+ γδ T cell repertoire, the first such analysis of its kind. These studies suggested the Vδ2negative repertoire in humans is diverse and largely private, but also highlighted a Vγ5Vδ1 population that was selectively detected in cytomegalovirus-seropositive individuals, and may be involved in cytomegalovirus immunity.
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Taner, Sabrina Beliz. "The role of lipid rafts in natural killer cell activation and immune surveillance". Thesis, Imperial College London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.423546.
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CASU, BEATRICE. "Analysis of novel tumor escape mechanisms from the Natural killer (NK) cells-mediated immune-surveillance". Doctoral thesis, Università degli studi di Genova, 2019. http://hdl.handle.net/11567/945499.
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Marchiori, Chiara. "The role of immune surveillance mechanisms acting to prevent an AOM - induced colorectal carcinogenesis progression". Doctoral thesis, Università degli studi di Padova, 2018. http://hdl.handle.net/11577/3425881.
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Colorectal cancer (CRC) is one of the most frequent cancer worldwide both in men and women. This tumour is the result of a multistep process in which there is a closed connection between the tumour development and immune system is the so-called immune surveillance, a dynamic process that comprises three different steps: elimination, equilibrium and escape. The hypothesis of my PhD project was that CD80 expression on dysplastic epithelial cells is crucial also in successful immune surveillance of sporadic colorectal cancer. The analysis of human colonic surgical specimens demonstrated that CD80 is over-expressed by epithelial cells in colonic pre-neoplastic lesions. Accordingly, also in our azoxymethane (AOM) induced colonic adenocarcinoma model, CD80 is overexpressed by dysplastic epithelial cells supporting a key role of this molecule in the early phases of the carcinogenesis process. Furthermore, the lack of functional CD80 in colonic mucosa accelerated the progression of colonic carcinogenesis. Remarkably, the use of CD80ko/WT bone marrow chimeras in the AOM CRC model further demonstrated the contribute of epithelial CD80 expression to inhibition of dysplasia development. Since AOM-induced carcinogenesis is associated to oxidative stress we hypothesized that CD80 expression is upregulated in intestinal epithelial cells by reactive oxygen species (ROS). Accordingly, our in vitro experiments with intestinal epithelial CT26 and primary intestinal epithelial cells suggested that oxidative stress has a prominent role in CD80 induction. Moreover, the thoughtful investigation of CD80 up regulation induced by ROS revealed that ROS induce CD80 expression via MAPK pathways that activate STAT3 transcription factor in colon epithelial cells. Thus, we showed that CD80 is crucial in the early stages of sporadic colorectal carcinogenesis and free radicals could have a prominent role in both the mechanisms of carcinogenesis and immune surveillance triggering the immune response. Besides, the microbiota signalling has a pivotal role in intestinal colon cancer carcinogenesis. In particular, Toll-like receptors seem to regulate a wide range of biological responses including inflammatory and immune responses during carcinogenesis. In detail, TLR4 signalling has been involved in the regulation of tumour growth, survival and progression connected to inflammation but its role is still controversial in non-inflammatory carcinogenesis. Along with the histological results showing that invasive carcinoma was more frequent in TLR4 deficient mice (TLR4KO) compared to Wild Type (WT) mice both sacrificed after 8 months from the first AOM injection, flow cytometric analysis revealed that MHC expression is impaired in intestinal epithelial cells of AOM-treated TLR4KO. Accordingly, the percentage of CD8+ cytotoxic and CD4+ helper T lymphocytes decreased in AOM-treated TLR4KO proposing a less efficient presentation of the tumoral antigens and the presence of a more effective immune escape mechanism compared to the WT mice. Since microbiota plays a key role to modulate immune cells activities we next compared the gut microbiota of WT and TLR4KO by 16S rDNA sequencing and analysis of faecal SCFA (Short Chain Fatty Acids) by GC-MS. Our results showed that WT and TLR4KO display a comparable composition of the microbiota, thus excluding that the differences observed in AOM-induced CRC development are secondary to microbiota differences, generating anomalous signals to mucosal immune cells. Indeed, in vitro experiments with bone marrow derived DCs confirmed the absolute requirement of TLR4 signalling to generate mature and competent DCs. Concluding, we showed that TLR4 signalling is protective in sporadic colorectal carcinogenesis enhancing the immune response against tumour cells. This result improves the understanding of TLR4-targeted applications, its role in tumor progression and its potential use as immune modulating agent.Il cancro al colon-retto (CRC) è uno dei tumori più frequenti in tutto il mondo sia negli uomini che nelle donne. Questo tumore è il risultato di un processo multistep in cui è presente un stretto legame tra il suo sviluppo e il sistema immunitario, la cosiddetta sorveglianza immunitaria, un processo dinamico che comprende tre diversi passaggi: eliminazione, equilibrio e fuga. Il nostro obbiettivo è stato di dimostrare che l'espressione di CD80 sulle cellule epiteliali displasiche è cruciale nel successo della sorveglianza immunitaria del CRC sporadico. I dati ottenuti dall'analisi dei pazienti dimostrano che il CD80 è sovraespresso dalle cellule epiteliali nelle lesioni pre-neoplastiche ma si riduce quando si è sviluppata una neoplasia Il CD80 è sovraespresso anche nelle prime fasi del processo di carcinogenesi nei topi trattati con AOM. Inoltre, la mancanza del CD80 funzionale nella mucosa accelera la progressione della carcinogenesi nel nostro modello murino e l'uso delle chimere supporta come l'espressione epiteliale di CD80 contribuisca all'inibizione dello sviluppo della displasia. I nostri risultati suggeriscono che l'espressione di CD80 è indotta quindi nelle lesioni preneoplastiche come meccanismo protettivo contro la degenerazione epiteliale indotta da AOM. Utilizzando la linea cellulare epiteliale intestinale CT26 e le cellule epiteliali intestinali primarie da topo, abbiamo accertato che lo stress ossidativo ha un ruolo fondamentale nell'induzione dell’espressione di CD80. Inoltre, i ROS nelle cellule epiteliali del colon inducono l'espressione di CD80 attraverso le vie attivate dalle MAP chinasi, le quali mediano la fosforilazione di STAT3. Abbiamo quindi dimostrato che il CD80 è fondamentale nelle fasi iniziali della carcinogenesi sporadica del CRC e che i ROS hanno un ruolo cruciale sia nei processi di carcinogenesi che di attivazione della sorveglianza immunitaria. Anche il microbiota ha un ruolo chiave nella carcinogenesi del cancro al colon, azione svolta probabilmente attraverso i recettori Toll-like. Nel dettaglio, il TLR4 è coinvolto nella regolazione della crescita, della sopravvivenza e della progressione tumorale connesse all'infiammazione, ma il suo ruolo è ancora controverso nella carcinogenesi non infiammatoria. Ecco che abbiamo messo in luce il ruolo protettivo dei segnali derivati dal recettore TLR4 nel modello di CRC indotto da AOM. Infatti, l’analisi istologica ha dimostrato una maggiore incidenza di carcinoma colico invasivo nei topi TLR4KO rispetto ai topi Wild Type. L'analisi citofluorimetrica ha rivelato che l'espressione del complesso maggiore di istocompatibilità I e II era alterata nei topi TLR4KO e parallelamente, la percentuale di linfociti T helper e citotossici era diminuita significativamente. Questi dati suggeriscono una minore presentazione degli antigeni tumorali da parte delle cellule epiteliali favorendo i meccanismi di fuga da parte delle cellule tumorali nei topi TLR4KO. Inoltre, abbiamo dimostrato nei topi TLR4KO un ridotto livello di cellule dendritiche mature critiche per l'attivazione delle cellule T antitumorali. Poiché il microbiota svolge un ruolo chiave nel modulare le attività delle cellule immunitarie, abbiamo confrontato il microbiota intestinale dei topi WT e TLR4KO mediante il sequenziamento dell'rDNA 16S e abbiamo quantificato gli acidi grassi a corta catena (SCFAs). I nostri risultati hanno mostrato che i due gruppi hanno una composizione comparabile del microbiota, confermando quindi che le differenze osservate non siano secondarie alla composizione del microbiota. Esperimenti in vitro utilizzando cellule dendritiche isolate dal midollo osseo hanno confermato la necessità del segnale proveniente dal TLR4 per ottenere cellule dendritiche mature e competenti. Concludendo, abbiamo dimostrato che il recettore TLR4 svolge un ruolo protettivo nella progressione della carcinogenesi colorettale sporadica, migliorando la risposta immunitaria.
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GILIOLI, DIEGO. "Dissecting the role of cellular senescence in acute myeloid leukaemia immune-surveillance and response to therapy". Doctoral thesis, Università Vita-Salute San Raffaele, 2022. http://hdl.handle.net/20.500.11768/133076.
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Pieper, Natalia [Verfasser] y Annette [Akademischer Betreuer] Paschen. "Impact of IFN-γ resistance & MAPK inhibition on the immune surveillance of malignant melanoma - relevance for immune-based therapies / Natalia Pieper ; Betreuer: Annette Paschen". Duisburg, 2019. http://d-nb.info/1201274095/34.
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Wischhusen, Jörg. "Resistance to apoptosis and escape from host immune surveillance two related (?) survival mechanisms of malignant glioma cells /". [S.l. : s.n.], 2004. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB11482185.
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Nougue, Manon. "Rôle immunomodulateur du système lymphatique lors du développement tumoral mammaire". Electronic Thesis or Diss., Toulouse 3, 2023. http://www.theses.fr/2023TOU30261.
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Le système lymphatique est un réseau vasculaire unidirectionnel transportant la lymphe qui permet le drainage des fluides interstitiels, le transport des lipides intestinaux, ainsi que la surveillance et la tolérance immunitaire. Néanmoins, le système lymphatique est impliqué dans de nombreuses pathologies et particulièrement dans la progression tumorale. En effet, le système lymphatique favorise la dissémination des métastases qui sont acheminées par les vaisseaux lymphatiques jusqu'aux organes distants. Plus récemment, le système lymphatique a été identifié comme un régulateur clé des réponses immunitaires lors du développement tumoral. Le système immunitaire est indispensable à la détection des tumeurs et à l'établissement de réponses lymphocytaires anti-tumorales. Cependant, lors des stades de développement tumoral avancés, des mécanismes d'échappement immunitaire se mettent en place en faveur de la croissance des tumeurs. Ces mécanismes sont notamment médiés par les tumeurs elles-mêmes mais aussi par différents acteurs de l'environnement tumoral. Le système lymphatique est un de ces acteurs, particulièrement retrouvé dans l'environnement tumoral mammaire. Les adénocarcinomes mammaires à des stades avancés répondent aux immunothérapies qui ciblent les points de contrôle immunitaire responsables de l'échappement immunitaire. En effet, le système lymphatique potentialise la réponse des tumeurs à ces immunothérapies car il joue un rôle double dans l'immunomodulation en contexte tumoral. Les vaisseaux lymphatiques sont capables de recruter les lymphocytes T dans la tumeur pour stimuler la surveillance immune anti-tumorale mais sont aussi capables d'engendrer des mécanismes immunosuppresseurs des lymphocytes T par l'expression de points de contrôle immunitaire. Durant de ma thèse, j'ai donc étudié les mécanismes immunomodulateurs du système lymphatique lors du développement des tumeurs mammaires. J'ai observé que le système lymphatique contrôle le passage de la surveillance immune vers l'immunosuppression, particulièrement induite par les ligands du point de contrôle immunitaire TIGIT. J'ai ainsi montré que l'activation des vaisseaux lymphatiques tumoraux entraine la surexpression du ligand Nectine-2 qui va inhiber les lymphocytes T surexprimant TIGIT. Cela va alors réduire la réponse des lymphocytes T CD8+ cytotoxiques afin de favoriser la croissance tumoraleThe lymphatic system is a unidirectional vascular network transporting lymph, enabling drainage of interstitial fluids, transport of intestinal lipids, and also immune monitoring and tolerance. Nevertheless, the lymphatic system is involved in many pathologies, and particularly in tumor progression. Indeed, the lymphatic system promotes the metastatic spread, carried by lymphatic vessels to distant organs. More recently, the lymphatic system has been identified as a key regulator of immune responses during tumor development. The immune system is essential for tumor detection and establishment of anti-tumor lymphocyte responses. However, at advanced stages of tumor development, immune escape mechanisms are established in favor of tumor growth. These mechanisms are mediated not only by tumors themselves, but also by various players in the tumor environment. The lymphatic system is one of these players, particularly found in breast tumor environment. Advanced-stage breast adenocarcinomas respond to immunotherapies that target immune checkpoints responsible for immune escape. Indeed, the lymphatic system potentiates tumor response to these immunotherapies, playing a dual role in immunomodulation in the tumor context. Lymphatic vessels are able to recruit T cells to the tumor site to stimulate anti-tumor immune surveillance, but are also able to generate T cell immunosuppressive mechanisms through the expression of immune checkpoints. During my thesis, I therefore studied immunomodulatory mechanisms of the lymphatic system during mammary tumor development. I observed that the lymphatic system controls a switch from immune surveillance to immunosuppression, particularly induced by ligands of TIGIT immune checkpoint. I have shown that activation of tumor lymphatic vessels leads to overexpression of Nectin-2, which inhibits T cells overexpressing TIGIT. This in turn reduces cytotoxic CD8+ T cell responses to promote tumor growth
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Hudspeth, K. L. "THE ROLE OF NATURAL CYTOTOXICITY RECEPTORS IN THE HOMEOSTASIS AND FUNCTION OF A NEWLY DISCOVERED SUBSET OF HUMAN GAMMA DELTA T CELLS". Doctoral thesis, Università degli Studi di Milano, 2013. http://hdl.handle.net/2434/218988.
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Natural Cytotoxicity Receptors (NCRs) were originally identified as specific natural killer cell activating receptors that, upon binding to their endogenous ligands, trigger the killing of tumor cell targets. Here we describe a population of Vδ1 + T cells from human peripheral blood that can differentiate in vitro to express the NCRs NKp30, NKp44 and NKp46. Moreover, we show that the expression of NKp30 endows Vδ1 + T cells with the ability to suppress HIV-1 viral replication and lyse hematologic tumor cells in vitro, through the production of CC chemokines and cytolytic granules, respectively. These experiments were also accompanied by the finding that a substantial population of Vδ1 + T cells within the intestinal epithelium expresses all three NCRs, with NKp46 being predominant. While the role for the NCR on expanded populations of γδ T cells from the peripheral blood grants γδ T cells with potent effector functions, we provide evidence that the NCR, and in particular NKp46, is a marker of hyporesponsive γδ T cells in the intestinal epithelium. These data suggest two opposing roles for the NCR on γδ T cells depending on the environment: 1) NCRs which can be induced in vitro are able to impart cytotoxic effector functions on the γδ T cells and 2) NCRs present in physiological conditions in the healthy intestine may function to regulate the γδ T cell. Our findings open exciting new avenues for the understanding of γδ IEL T cell function. Moreover, the induction of NCRs on peripheral γδ T cells in vitro may have direct implications in the development of adoptive cell therapies for the treatment of various diseases including cancer and HIV-1 infection.
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Enzler, Thomas. "GM-CSF and IFN-[gamma] [IFN-gamma] deficiency link autoimmune diseases and cancer a cancer immune surveillance controversy /". [S.l.] : [s.n.], 2004. http://www.diss.fu-berlin.de/2004/153/index.html.
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Du, Page Michel Justin Porter. "Investigation of T cell-mediated immune surveillance against tumor-specific antigens in genetically engineered mouse models of cancer". Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/62620.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2011.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis. Vita.
Includes bibliographical references.
The association of tumor cells and lymphocytes has led to the hypothesis that our immune system actively inhibits the formation and progression of cancer, a phenomenon called tumor immune surveillance. T cells specific to mutant proteins have been identified in cancer patients and the recent success of cancer immunotherapies provides evidence that the immune system can fight this disease. Yet the frequent occurrence of malignant disease despite T cell recognition presents a significant medical problem. Only after we determine how tumors bypass the immune system can immunotherapeutic approaches be improved. To understand how tumors subvert immune responses, tumor transplantation or transgenic mice expressing tumor-associated antigens have been used to model cancer. To assess the role of anti-tumor T cells in models that more accurately reflect the human disease, I developed new systems to introduce exogenous antigens, to mimic neoantigens, into genetically engineered mouse models of lung cancer and sarcomas. Utilizing the mouse model of lung cancer, I show that endogenous T cells respond to and infiltrate lung tumors, delaying malignant progression. Despite continued antigen expression, T cell infiltration does not persist and tumors ultimately escape immune attack. Transplantation of cell lines derived from lung tumors that express these antigens or prophylactic vaccination against autochthonous tumors, however, results in rapid tumor eradication or selection of tumors that lose antigen expression. These results support clinical data that suggest a role for the immune system in cancer suppression rather than prevention. Tumor immune surveillance and immunoediting have largely been defined using carcinogen-driven models of sarcomagenesis. Using a genetically engineered model of sarcomagenesis, I show that immunoediting requires potent T cell antigens and that lymphocytes drive the evolution of less immunogenic tumors by selecting for antigen loss. Finally, immunotherapies have historically been ineffective in treating cancer patients. I show that vaccination against specific antigens expressed in mouse lung cancers leads to sustained anti-tumor T cell responses that eradicate recently initiated tumors. Vaccination also stimulates anti-tumor T cell responses in an antigen-independent fashion by enhancing the expansion and activity of T cells that recognize antigens only expressed in tumors.
by Michel Justin Porter Du Page.
Ph.D.
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Joshi, Urjita [Verfasser] y Bernd [Akademischer Betreuer] Engelmann. "Role of extracellular vesicles, microvascular fibrin formation and immune surveillance in pancreatic cancer metastasis / Urjita Joshi ; Betreuer: Bernd Engelmann". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1191097951/34.
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DI, CAMILLO FEDERICA. "Analisi degli effetti del miR-30d sulla via di segnalazione immune cGAS/STING/IFN-I in cellule di carcinoma mammario". Doctoral thesis, Università degli Studi di Trieste, 2023. https://hdl.handle.net/11368/3042422.
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I tumori sono ecosistemi complessi, nei quali popolazioni eterogenee di cellule tumorali sono immerse in un microambiente dinamico. La comunicazione delle cellule tumorali con il microambiente causa effetti protumorigenici sia locali che sistemici, tra cui l’angiogenesi, il rimodellamento della matrice extracellulare, e la modulazione della componente immunitaria/infiammatoria, supportando la progressione tumorale e l’evasione dalla sorveglianza immunitaria. La comprensione dei meccanismi di evasione dal sistema immunitario è di particolare importanza per migliorare l'efficacia delle immunoterapie antitumorali. È noto che oncogeni, quali le forme mutate di p53 (mut-p53) e HIF1α, contribuiscono all'evasione immunitaria attraverso l’inibizione della cascata di segnalazione di cGAS/STING/IFN-I nelle cellule tumorali. Questa via è iniziata dall’attivazione di cGAS da DNA citoplasmatico, con conseguente traslocazione di STING dal reticolo endoplasmatico al Golgi, attivazione del fattore di trascrizione IRF3 ed espressione dei geni della risposta all’interferone di tipo-I (IFN-I), i quali codificano per immunomodulatori che innescano la sorveglianza immunitaria antitumorale. Recentemente, il nostro gruppo di ricerca ha evidenziato un meccanismo oncogenico che influenza la comunicazione tra le cellule tumorali e quelle stromali. Abbiamo scoperto che il miR-30d, un miRNA oncogenico secreto indotto da HIF1α e mut-p53, causa alterazioni strutturali dell’apparato di Golgi. Ciò promuove la secrezione tumorale ed altera il microambiente favorendo la crescita tumorale e la colonizzazione metastatica.
L'analisi trascrittomica di cellule di carcinoma mammario (CM) metastatico in seguito al silenziamento del miR-30d ha suggerito l'ipotesi che livelli elevati di miR-30d possano inibire l'espressione dei geni IFN-I, una condizione che potrebbe contribuire a inibire la risposta immune antitumorale.
In questo lavoro di tesi ho studiato l'impatto del miR-30d nella regolazione della cascata di segnalazione di cGAS/STING/IFN-I e i meccanismi attraverso i quali il silenziamento del miR-30d porta all’induzione di tale segnalazione in cellule di CM. In particolare, ho dimostrato che l'inibizione del miR-30d porta all'attivazione dei principali componenti del macchinario di segnalazione cGAS/STING, in particolare induce la fosforilazione di TBK1 e STING, la traslocazione nucleare di IRF3 e la conseguente secrezione di interferoni di tipo¬-I. Gli effetti dell'inibizione del miR-30d includono la normalizzazione della struttura del Golgi e la concomitante attivazione di STING nel Golgi. Ciò suggerisce che il miR-30d potrebbe inibire la via cGAS/STING inducendo alterazioni strutturali dell’apparato del Golgi. Inoltre, abbiamo riscontrato che l'inibizione del miR-30d nelle cellule di CM promuove danno al DNA nucleare e accumulo di DNA nel citoplasma, con conseguente attivazione di cGAS. In sintesi, i nostri risultati sono coerenti con un modello in cui l'inibizione del miR-30d contribuisce ad innescare l'induzione della via cGAS/STING in cellule tumorali attraverso il rilascio di DNA nel citosol, ed inoltre a promuoverne l’attivazione attraverso la normalizzazione della struttura del Golgi.
Ho inoltre osservato che la combinazione di inibitori del miR-30d con agenti chemioterapici in cellule di CM ha un effetto sinergico nell’attivazione di IFN-I. Sono attualmente in corso esperimenti mediante modelli preclinici ex-vivo e in-vivo per verificare se l'inibizione di miR-30d possa riattivare la sorveglianza immunitaria, e per valutare l’effetto della combinazione di inibitori di miR-30d con trattamenti chemioterapici che inducono cGAS/STING/IFN-I.Tumors are complex ecosystems composed by heterogeneous populations of cancer cells embedded in a dynamic tumor microenvironment (TME). Communication of cancer cells with the TME displays both local and systemic tumor-promoting effects, including angiogenesis, ECM remodeling, and modulation of immune/inflammatory cells, to support tumor growth and progression, and escape from immune surveillance. Understanding immune evasion mechanisms that generate non-immunogenic “cold” tumors represents a key issue for improving the efficacy of anticancer immune therapies. Accumulating evidence has established that oncogenic drivers, such as mutant p53 and HIF1α, contribute to tumor progression and immune evasion by attenuating the cGAS/STING/IFN-I pathway in cancer cells. This cascade involves cGAS-dependent sensing of cell-intrinsic DNA damage with consequent induction of STING ER-Golgi trafficking, activation of the transcription factor IRF3 and expression of downstream type-I interferons (IFN) response target genes, thus engaging anti-tumor immune surveillance. Recently, our research group highlighted an oncogenic axis affecting tumor-stroma crosstalk. We discovered that miR-30d, a secreted onco-miRNA cooperatively induced by HIF1α and mutp53 oncoproteins, regulates targets involved in the secretory pathway, causing structural alterations of ER and Golgi compartments. This promotes the release of a pro-malignant secretome, which alters the TME and fosters tumor growth and metastatic colonization. Transcriptomic analysis in metastatic breast cancer (BC) cells upon downregulation of miR-30d highlighted a putative inhibitory effect of miR-30d on the categories of “cellular response to DNA damage”, “type-I interferon production” and “antiviral innate immune response”, leading to the hypothesis that high levels of miR-30d might inhibit the expression of type-I IFN target genes, a condition that could contribute to establish an immune “cold” microenvironment. In this work I have investigated the impact of miR-30d on the regulation of IFN response and dissected the mechanisms by which ablation of miR-30d leads to upregulation of IFN signaling in BC cells. By using an LNA inhibitor and a miR-30d Decoy construct, I have demonstrated that inhibition of miR-30d in BC cells led to activation of the main components of the cGAS/STING signaling machinery, in particular phosphorylation of TBK1 and STING, nuclear translocation of the IRF3 transcription factor, and consequent secretion of type-I IFNs. The effects of miR-30d inhibition included normalization of fragmented Golgi structure, and concomitant activation of STING at Golgi apparatus in BC cells, thus suggesting that miR-30d might attenuate the cGAS/STING pathway by inducing structural alterations of the secretory pathway, in particular of the Golgi. Furthermore, I found that miR-30d inhibition in BC cells promoted accumulation of nuclear DNA damage and of cytoplasmic dsDNA with activation of cGAS, which acts upstream of the STING DNA-sensing pathway. In sum, this evidence is consistent with a model in which inhibition of miR-30d may both trigger upstream induction of the cGAS/STING pathway in cancer cells, by causing release of dsDNA in the cytosol, and further sustain its activity by normalizing the structure of the secretory pathway. In addition, I observed that when miR-30d inhibition was combined with conventional chemotherapeutic agents in metastatic BC cells, the treatment led to a much stronger effect on the activation of the IFN signaling. Experiments with ex-vivo and in-vivo preclinical models are currently in progress to investigate whether inhibition of miR-30d could reactivate immune surveillance as well as to test synergies between miR-30d inhibition and cGAS/STING-inducing chemotherapeutic treatments.
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Gonçalves, Maia Maria João. "Le syndrome Xeroderma Pigmentosum : Un nouveau modèle pour l’étude du rôle des fibroblastes dans la modulation de la réponse immunitaire innée contre les cellules cutanées cancéreuses". Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2019. http://www.theses.fr/2019AZUR4037.
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L’étiologie des cancers cutanées est liée à des mutations génétiques résultant de l’exposition aux rayonnements ultraviolets (UV) émis par le soleil. La propagation des cellules cancéreuses dépend aussi des interactions avec les cellules présentes dans le microenvironnement circulant, notamment des fibroblastes associés au cancer (FAC) et des cellules immunitaires. Xeroderma pigmentosum (XP) est une maladie génétique qui comprend 7 groupes de complémentation génétique (XP-A à XP-G). Les patients XP présentent une déficience du mécanisme de réparation des lésions de l’ADN provoquées par les UV. Ces patients sont susceptibles au développement précoce de très nombreux cancers cutanées. XP-C est le groupe de complémentation le plus représenté en Europe. Chez ces patients, les carcinomes spino-cellularies (CSC) sont plus fréquents que les carcinomes baso-cellulaires (CBC) (taux 5 : 1). Les CSC ont un potentiel métastatique plus élevé que les CBC. Des travaux précédents ont suggéré que la réponse immunitaire chez les patients XP pouvait être altérée, incluant un déficit de l’activité cytolytique des cellules Natural Killer (NK) et une diminution du nombre des lymphocytes T circulants.L’objectif central de cette thèse était, d’identifier des facteurs du microenvironnement impliqués dans la progression des cancer cutanées agressifs, en prenant comme modèle de susceptibilité au cancer, des cellules de patients XP-C. Une analyse transcriptomique comparant les fibroblastes WT et des patients XP-C a permis d’identifier que CLEC2A, un ligand activateur du récepteur NKp65 des cellules NK, est exprimé par les fibroblastes WT mais pas par les fibroblastes XP-C. Nos travaux ont pu montrer une diminution du niveau d’expression de CLEC2A au cours de la sénescence réplicative ; une absence dans les FAC et dans les CSC et que, des facteurs solubles secrétés para les CSC diminuent l’expression de CLEC2A. Ces résultats suggèrent que la perte de CLEC2A peut induire un déficit d’activation des cellules NK au sein du microenvironnement tumoral et dans les dermes des patients XP-C. Par la suite, nous avons élaboré un modèle de culture de peau 3D, dans lequel nous avons introduit des cellules NK, en présence ou absence d’anticorps bloquants CLEC2A. Ce modèle nous a permis de montrer que l’interaction CLEC2A/NKp65 régule l’invasion des CSC via un dialogue entre fibroblastes et cellules NK. Nos résultats suggèrent que l’expression de CLEC2A dans les fibroblastes WT contribue à la surveillance immunitaire dans la peau et que son absence, par des facteurs encore inconnus, favorise le développement des cancers agressifs chez les patients XP-C. CLEC2A peut être une cible dans le combat contre la progression des CSCSkin cancer etiology is related to genetic mutations arising after ultraviolet (UV) sun exposure. The propagation of cancer cells is also dependent of a crosstalk with cells present in the surrounding microenvironment, mainly cancer associated fibroblasts (CAF) and immune cells. Xeroderma pigmentosum (XP) is a genetic disease that comprises seven groups of genetic complementation (XP-A to XP-G). XP patients present a default in the mechanism responsible for the repair of UV-induced DNA lesions. They are prone to develop skin cancers with high frequencies early in their life. XP-C is the most represented complementation group in Europe and in XP-C patients squamous cell carcinoma (SCC) are more frequent than basal cell carcinoma (BCC) (ratio 5:1). SCC have high metastatic potential compared to BCC. Previous studies suggested that the immune responses in XP patients could be altered with defects in their NK lytic activity and a decrease in the levels of circulating T lymphocytes. The main objective of this thesis was to identify microenvironment factors that could contribute to the progression of aggressive skin cancers using XP-C disease cells as a model of skin cancer susceptibility. Comparative transcriptomic analysis of WT and XP-C dermal patient’s fibroblasts revealed that CLEC2A, a ligand of the activating NK receptor NKp65 implicated in the activation of the innate immune system, is expressed in WT fibroblasts and absent in XP-C fibroblasts. Additional work showed that CLEC2A level is decreased in WT fibroblasts during replicative senescence, is absent in CAF and SCC, and is down regulated by soluble factors secreted by SCC cells. These results suggest that the loss of CLEC2A may induce a deficit of NK cell activation in the tumor microenvironment of SCC and in the dermis of XP-C patients. Elaboration of 3D skin culture models including NK cells and, in the presence or absence of blocking anti-CLEC2A antibody, allowed us to show that CLEC2A/NKp65 interaction regulates SCC cells invasion through a crosstalk between fibroblasts and NK cells. Our results suggest that the expression of CLEC2A in fibroblasts contributes to skin immune surveillance while, conversely, its absence under yet unidentified factors, favors the development of aggressive cancers in XP-C patients. CLEC2A could be a potential target in the fight against SCC progression
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Pereira, Abrantes Manuela. "Hétérogénéité des neutrophiles et leurs écosystèmes dans l’immunosurveillance au cours de la tumorigenèse". Electronic Thesis or Diss., Lyon 1, 2023. http://www.theses.fr/2023LYO10147.
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Le neutrophile est la cellule immunitaire la plus représentée dans le sang chez l’Homme, dont la migration au site inflammatoire est rapide. Le rôle du neutrophile a largement été décrit dans des contextes infectieux, auto-immunitaires et allergiques mais reste controversé dans le cancer, notamment dans les mécanismes d’immunosurveillance précoce. Le neutrophile se révèle être une population hétérogène tant phénotypiquement que fonctionnellement. L’origine et la compréhension de l’hétérogénéité des neutrophiles est un sujet émergent et croissant, mais aucune étude à ce jour ne décrit l’évolution de l’hétérogénéité des neutrophiles à différents stades. L’objectif de ma thèse est de caractériser cette hétérogénéité au sein des tissus au cours de la tumorigenèse, à partir de deux modèles d’études. Mon premier projet s’est intéressé au cancer colorectal (CCR) chez l’Homme de par l’accès privilégié à des échantillons de tissus adjacents colorectaux (AT), de tissus prénéoplasiques (polypes, P) et d'adénocarcinomes (ADK), frais, synchrones et pairés à partir de patients subissant des colectomies partielles ou totales. Des quantifications protéomiques démontrent que les neutrophiles représentent la principale augmentation de cellules immunitaires innées au sein de l'ADK. Pour la première fois, les profils transcriptomiques de neutrophiles triés et de leurs partenaires cellulaires par RNA-seq et single cell RNA-seq (scRNA-seq) au cours de la tumorigenèse ont été établis et intégrées pour déchiffrer l'hétérogénéité, l’évolution et les interactions cellulaires clés des neutrophiles, au cours du CCR. Alors que le microenvironnement du P et de l’ADK sont similaires et distinct de l’AT, le transcriptome des neutrophiles de P et d’AT sont corrélés mais différents de ceux de l’ADK. Ces résultats suggèrent une niche pré-inflammatoire dans le P favorable aux modifications des neutrophiles, précédant l'inflammation cancéreuse, favorisant la migration et l’activation des cellules myéloïdes. Les neutrophiles du P présentent des propriétés fonctionnelles (e.g. dégranulation, activation, production de cytokines) tandis que les neutrophiles de l'ADK présentent un état “d’épuisement” associé à un profil plutôt pro-tumoral (i.e. perte de fonctions canoniques et profil pro-tumoral). Le scRNA-seq de neutrophiles triés identifie 8 clusters distincts, dont deux sont spécifiquement enrichis dans l’AT et l’ADK. Le cluster enrichi dans l’AT est associé à des signatures anti-tumorales tandis que le cluster associé à l'ADK démontre des caractéristiques pro-tumorales, basées sur des analyses d’enrichissement de signatures issues de données publiques. Les analyses de trajectoire démontrent un continuum de l’AT, à P et ADK avec 3 trajectoires distinctes, où un cluster unique de neutrophiles exprimant des gènes induits par les interférons et enrichi dans l’ADK se distingue des autres. Le second projet s’est basé sur un modèle murin de carcinogenèse mammaire spontanée MMTV-NeuT pour lequel, à la différence du modèle chez l’Homme, nous avons accès aux différents stades tumoraux mais également au sang et aux organes lymphoïdes primaire (moelle osseuse) et secondaire (rate). Les analyses transcriptomiques de neutrophiles triés révèlent des états phénotypiques et fonctionnels distincts selon l’organe et le stade tumoral analysé. De manière originale, nous avons mis en évidence l’existence de neutrophiles EpCAM+ uniques aux tissus tumoraux et constituant 60 à 90% des neutrophiles totaux au cours de la tumorigenèse. L’expression d’EpCAM n’est pas endogène mais semblerait provenir de fragments membranaires exogènes à la surface du neutrophile, suggérant un mécanisme de trogocytose voire de trogoptose des cellules prénéoplasiques et tumorales. De futures études fonctionnelles permettront d’élucider le mécanisme et le rôle des neutrophiles EpCAM+The neutrophil is the most abundant immune cell in the human blood that migrates rapidly to the inflammatory site. The role of neutrophils has been extensively described in infectious, autoimmune, and allergic contexts, but it remains controversial in cancer, particularly in early immune surveillance mechanisms. Neutrophils are a heterogeneous population, both phenotypically and functionally. The origin and understanding of neutrophil heterogeneity are emerging and increasingly studied, albeit to date, no study has described the evolution of neutrophil heterogeneity at different stages. The aim of my thesis is to characterize this heterogeneity within tissues during tumorigenesis, using two models. My first project focused on colorectal cancer (CRC) in humans, taking advantage of a privileged access to fresh, synchronous, and paired adjacent colorectal tissue samples (AT), preneoplastic tissues (polyps, P), and adenocarcinomas (ADK), from patients undergoing partial or total colectomies. Proteomic quantification demonstrated that neutrophils represent the main increase in the innate immune compartment within ADK. For the first time, transcriptomic profiles of FACS-sorted neutrophils and their cellular partners using RNA-seq and single-cell RNA-seq (scRNA-seq) throughout tumorigenesis were established and integrated to decipher the heterogeneity, evolution, and key cellular interactions of neutrophils in CRC. While the microenvironment of P and ADK were similar and distinct from AT, the transcriptome of P and AT neutrophils were correlated but different from ADK-associated neutrophils. These results suggest a pre-inflammatory niche in P that favors neutrophil modifications, preceding cancer-related inflammation, promoting migration and activation of myeloid cells. P-associated neutrophils exhibited functional properties (e.g. degranulation, activation, cytokine production), while ADK-associated neutrophils showed an "exhausted" state associated with a more pro-tumoral profile (i.e. loss of canonical functions and pro-tumoral profile). scRNA-seq of FACS-sorted neutrophils identified 8 distinct clusters, two of which were specifically enriched in AT and ADK. The AT-enriched cluster was associated with anti-tumoral signatures, while the ADK-enriched cluster demonstrated pro-tumoral characteristics, based on enrichment analyses of publicly available data signatures. Trajectory analyses showed a continuum from AT to P and ADK with three distinct trajectories, where a unique ADK-enriched cluster of neutrophils expressing interferon-stimulated genes stood out from the others. The second project was based on a mouse model of spontaneous mammary carcinogenesis, MMTV-NeuT, for which, unlike the human model, we have access to breast tissues at different stages as well as blood and primary (bone marrow) and secondary (spleen) lymphoid organs. Transcriptomic analysis of FACS-sorted neutrophils revealed distinct phenotypic and functional states depending on the organ and tumor stage. Interestingly, we unveiled the existence of a unique EpCAM+ neutrophil population in tumor tissues, representing 60 to 90% of total neutrophils throughout tumorigenesis. EpCAM expression was not endogenous but seemed to originate from exogenous membrane fragments on the surface of neutrophils, suggesting a mechanism of trogocytosis or even trogoptosis of preneoplastic and tumor cells. Further functional studies will elucidate the mechanism and the role of EpCAM+ neutrophils
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Marchand, Adrien. "Pertinence écologique des biomarqueurs d'immunotoxicité en surveillance environnementale . Evaluation of chlorpyrifos effects, alone and combined with lipopolysaccharide stress, on DNA integrity and immune responses of three-spined stickleback, Gasterosteus aculeatus". Thesis, Reims, 2018. http://www.theses.fr/2018REIMS049.
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Ce travail propose d’améliorer les connaissances sur la variabilité naturelle des immunomarqueurs cellulaires innées chez un poisson modèle en écotoxicologie, l’épinoche à trois-épines, Gasterosteus aculeatus. Il a pour but la détermination de valeurs de référence utilisables dans un contexte de biosurveillance passive pour chacun des immunomarqueurs considérés. Ainsi, l’effet de trois facteurs confondants, que sont la période de prélèvement, la taille et le sexe des organismes, a été étudié en conditions contrôlées de laboratoire. Il a été ainsi possible d’obtenir, pour chaque immunomarqueur, un modèle donnant sa valeur moyenne en fonction des trois facteurs confondants, ainsi qu’une plage de valeurs de référence laboratoire. Dans une optique d’utilisation en biosurveillance, il est important de savoir si ce modèle laboratoire peut être utilisé dans d’autres conditions. Dans un second temps, les plages de référence laboratoire ont été confrontées à des données issues de poissons élevés en conditions semi-naturelles (condition mésocosme) et à des données in situ d’un site témoin (condition terrain). Les résultats de cette confrontation ont permis la construction d’un modèle prédictif des variations naturelles des immunomarqueurs dans chaque condition expérimentale. Testées dans un contexte de biosurveillance, l’utilisation des plages de référence terrain a bien montré la capacité de discriminer les sites témoins et contaminés. De plus, cette méthode a favorisé la la détection de faux positifs, induits par une hétérogénéité morphologique des poissons prélevés sur les différents sites, issus des résultats obtenus avec des procédures statistiques classiquesThe natural variability of cellular innate immunomarkers in a model species in ecotoxicology, the three-spined stickleback, Gasterosteus aculeatus was studied in order to determine immunomarker reference values useful for passive biomonitoring Thus, effects of three confounding factors, sampling period, sex, and fish body size, were investigated in controlled laboratory conditions. This first phase enabled the construction of a mathematical model that predicts immunomarker mean values in function of the three considered confounding factors, along with a range of reference values in laboratory conditions. To be used for biomonitoring, it is important to know if the laboratory model is correctly predicting other conditions. Therefore, laboratory reference ranges were compared to data obtained from fish sampled in semi-natural conditions (mesocosm conditions) and fish sampled in natural conditions, in one uncontaminated site (field condition). Results of this comparison allowed to construct a predictive model of the natural variations of immunomarker values in each experimental condition. Tested in a biomonitoring context, the use of field reference range allowed to i) discriminate between contaminated and uncontaminated sites and ii) identify false positives that are due to the morphological heterogeneity of fish sampled in the different sites
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Perroud, Junior Mauricio Wesley 1971. "Avaliação de viabilidade, tolerância e segurança da vacina com células dendríticas autológas maduras em pacientes com carcinoma de pulmão não pequenas células avançado = Assessment of feasibility, safety and tolerance of mature autologous dendritic cells vaccine in patients with advanced non-small cell lung carcinoma". [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310256.
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Orientador: Lair ZambonTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-21T10:28:19Z (GMT). No. of bitstreams: 1 PerroudJunior_MauricioWesley_D.pdf: 9913138 bytes, checksum: 5dd1ec64b004b6d50e2392e6383c9c98 (MD5) Previous issue date: 2012
Resumo: Os resultados terapêuticos globais do carcinoma de pulmão não pequenas células em estádio avançado são bem limitados. A imunoterapia com células dendríticas foi desenvolvida como uma nova estratégia para o tratamento de câncer de pulmão. O objetivo deste estudo foi avaliar a viabilidade, segurança e respostas imunológicas em pacientes com carcinoma de pulmão não pequenas células tratados com vacina autóloga de células dendríticas maduras pulsadas com antígenos. Cinco pacientes HLA-A2 com carcinoma de pulmão não pequenas células inoperável (estádio III ou IV) foram selecionados para receber duas doses de 5 x 107 de células dendríticas administradas por vias subcutânea e intravenosa, duas vezes em intervalos de duas semanas. A segurança, tolerabilidade e respostas imunológica e tumoral à vacina foram avaliadas pela evolução clínica e laboratorial, ensaio de linfoproliferação e critérios de RECIST, respectivamente. A dose utilizada para a imunoterapia demonstrou ser segura e bem tolerada. O ensaio de linfoproliferação mostrou uma melhora na resposta imune específica após a imunização, com uma resposta significativa após a segunda dose (p = 0,001). Esta resposta não foi persistente e houve uma tendência à redução após duas semanas da segunda dose da vacina. Dois pacientes apresentaram uma sobrevida quase duas vezes maior que a média esperada e foram os únicos que expressaram os antígenos tumorais HER-2 e CEA Apesar do pequeno tamanho da amostra, os resultados sobre o tempo de sobrevida, resposta imune, segurança e tolerabilidade, combinado com os resultados de outros estudos, são animadores para a condução de um estudo clínico com doses múltiplas em pacientes com câncer de pulmão que foram submetidos a tratamento cirúrgico, seguindo as diretrizes do Cancer Vaccine Clinical Trial Working Group
Abstract: Overall therapeutic outcomes of advanced non-small-cell lung cancer (NSCLC) are poor. The dendritic cell (DC) immunotherapy has been developed as a new strategy for the treatment of lung cancer. The purpose of this study was to evaluate the feasibility, safety and immunologic responses in use in mature, antigen-pulsed autologous DC vaccine in NSCLC patients. Five HLA-A2 patients with inoperable stage III or IV NSCLC were selected to receive two doses of 5x107 DC cells administered subcutaneous and intravenously two times at two week intervals. The safety, tolerability and immunologic and tumor responses to the vaccine were evaluated by the clinical and laboratorial evolution, lymphoproliferation assay and RECIST's criteria, respectively. The dose of the vaccine has shown to be safe and well tolerated. The lymphoproliferation assay showed an improvement in the specific immune response after the immunization, with a significant response after the second dose (p = 0.001). This response was not long lasting and a tendency to reduction two weeks after the second dose of the vaccine was observed. Two patients had a survival almost twice greater than the expected average and were the only ones that expressed HER-2 and CEA together. Despite the small sample size, the results on the survival time, immune response, and safety and tolerability, combined with the results of other studies, are encouraging to the conduction of a large clinical trial with multiples doses in patients with early lung cancer who underwent surgical treatment, following the guidelines of the Cancer Vaccine Clinical Trial Working Group
Doutorado
Clinica Medica
Doutor em Ciências
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Rorat, Agnieszka. "Assessment of the vermicomposting process applied to sewage sludge by monitoring of the compost quality and immune responses of three earthworm species : Eisenia fetida, Eisenia andrei and Dendrobaena veneta". Thesis, Lille 1, 2015. http://www.theses.fr/2015LIL10165.
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Le vermicompostage est une éco-biotechnologie relativement nouvelle qui utilise des vers de terre comme bioréacteurs naturels dans un procéssus de décomposition de la matière organique. En Europe, on utilise trois espèces d’annélides oligochètes : Eisenia fetida, Eisenia andrei et Dendrobaena veneta. Compte tenu des directives de l’Union Européenne portant sur le traitement des déchets, les contenus en métaux lourds, en composés chimiques divers et en microorganismes pathogènes des boues d’épuration ne permettent pas leur valorisation directe en agriculture. La qualité du produit obtenu après vermicompostage peut être évaluée en utilisant des paramètres agronomiques, tandis que des paramètres immunitaires et de défense mesurés chez les vers permettent d’apprécier l’impact des contaminants sur ces organismes du sol. Les objectifs de ce travail étaient: 1) apprécier l'influence des vers de terre sur la qualité du produit final dans le processus de lombricompostage, 2) examiner les mécanismes moléculaires et immunologiques mis en œuvre chez les lombrics au cours du lombricompostage de boues d'épuration urbaines, 3) de développer le compostage combiné au processus de lombricompostage. Les vers de terre utilisés dans les travaux présentés ont été classés en trois espèces grâce à la technique de barcoding moléculaire. Les fluorophores sélectionnés ont été testés comme les biomarqueurs spécifiques à l’espèce. Le contenu en riboflavine, le nombre de coelomocytes (amébocytes/éléocytes) et le niveau d’expression de gènes sélectionnés ont été utilisés comme biomarqueurs de stress permettant la bio-oisurvéillance du processus. La technique appliquée a conduit à évaluer les possibilités de valorisation des boues d'épurationVermicomposting is a relatively new eco-biotechnology using earthworms as natural bioreactors in the process of decomposition of organic matter. Eisenia andrei, Eisenia fetida and Dendrobaena veneta are detrivorous organisms that enhance the decomposition of complex organic compounds and influence circulation of organic matter. This eco-technique is a non-expensive method of biodegradation of organic wastes, inter alia sewage sludge. Due to the high content of various pollutants, including heavy metals, chemicals and pathogenic microorganisms, sewage sludge cannot be directly used in agriculture. The quality of the product can be assessed using agronomic parameters, while immune and defense parameters can be measured as stress biomarkers. Aims of this work were: 1) to determine the influence of earthworms on the quality of the product obtained in vermicomposting process, 2) to investigate the molecular and immunological mechanisms occurring in earthworms during vermicomposting of municipal sewage sludge, 3) to develop the combined composting – vermicomposting process. Earthworms were segragated into three separate groups basing on DNA barcoding and selected fluorophores were tested as non-invasively retrieved biomarkers allowing distinction between morphologically similar composting earthworm species. Riboflavin, coelomocytes (amoebocytes/eleocytes) composition and particular gene expression levels were selected as biomarkers of stress useful in biomonitoring of the vermicomposting process. Applied technique has led to assess the possibilities of valorization of sewage sludge
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Levy, Jonathan. "Étude du rôle de l’autophagie dans la cancérogenèse intestinale". Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T049/document.
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Considéré comme un cancer de l'âge mûr, l'incidence du cancer colorectal ne cesse d'augmenter avec l'allongement de la vie. Dans la majorité des cas, le cancer colique est associé à une mutation du gène suppresseur de tumeur Apc, contrôlant l’activation de la signalisation Wnt/β-caténine. Afin, d'identifier de nouveaux acteurs de la tumorigenèse colique, notre laboratoire a développé des modèles murins de mutation du gène Apc qui ont pour avantage de mimer la pathologie humaine (Colnot et al, 2004 ; Andreu et al, 2005). La création de ces modèles a permis à l’équipe de démontrer i) qu’une activation physiologique de cette voie contrôle la prolifération des cellules souches et des progéniteurs ainsi que leur différenciation et ii) qu’une activation aigüe est suffisante pour déclencher l’initiation tumorale intestinale (Andreu et al, 2005; Andreu et al, 2008). Les travaux antérieurs à mon arrivée ont permis d’identifier différents évènements moléculaires et cellulaires induits en cascade suite à l’activation pathologique de la voie Wnt/β-caténine. Parmi ceux-ci, une induction transcriptionnelle de gènes impliqués dans l'autophagie a été mise en évidence. Ce processus d'auto-cannibalisme cellulaire est associé à de nombreuses pathologies telles que les maladies neurodégénératives ou infectieuses. Cependant, le rôle de l'autophagie dans le cancer reste ambivalent et son implication dans le cancer colique demeure inconnue.Dans ce contexte, mon travail de doctorat a consisté à répondre aux questions suivantes :L’induction transcriptionnelle de gène Atg s’accompagne-t-elle d’une activation du processus d’autophagie à tous les stades de la progression tumorale intestinale murine et humaine?Des études de transcriptomique à haut débit nous ont permis d’identifier une induction transcriptionnelle de gènes clés du processus d’autophagie tels qu’Atg7. Cependant, l’activation fonctionnelle de l’autophagie n’est pas toujours associée à une augmentation de la transcription des acteurs de ce processus. Nous nous sommes donc intéressés aux marqueurs couramment décris dans la littérature et permettant d’établir l’état d’activation du flux autophagique. Ainsi, nous avons étudié le niveau d’expression de ces marqueurs par des expériences de western-blot et d’immuno-marquages sur des échantillons tumoraux humains et murins à différents stades de la progression du CRC. L’inhibition de l’autophagie impacte-t-elle la carcinogénèse colorectale?Dans ce contexte, nous avons généré un modèle murin de délétion conditionnelle et simultanée d'un allèle du gène Apc et des deux allèles du gène Atg7 (gène clé de l'autophagie) spécifiquement dans les cellules épithéliales intestinales. Afin de suivre l'apparition et l'évolution des tumeurs au cours du temps, nous avons mis au point une nouvelle méthode non-invasive de reconstruction tridimensionnelle de côlons de souris, issue d'imagerie échographique à haute résolution. Dans le but de caractériser l’impact de l’inhibition de l’autophagie, les modifications propres à la cellule déficiente en autophagie ont été explorées, notamment le statut énergétique ainsi que les changements dans l’environnement immunitaire et microbien de l’épithélium intestinal. Finalement, l’inhibition génétique de l’autophagie dans notre modèle murin, prédisposé au développement de tumeurs intestinales, nous a permis de caractériser l’implication de l’autophagie dans la carcinogénèse colique, ainsi que les mécanismes moléculaires et cellulaires liant l’auto-cannibalisme cellulaire à la pathologie tumoraleColorectal cancer is one of the major causes of cancer-related deaths. We took advantage of Apc mutant mice that mimic the adenomatous polyps that affect humans with an inactivated Apc gene, to gain insight into the critical events that affect the development of colorectal cancer. We show that autophagy, a catabolic pathway involved in the degradation of intracellular proteins and organelles, is activated in intestinal murine and human cancer and its inhibition has a crucial role in controlling tumorigenesis. We report that the in vivo conditional deletion of the essential autophagy gene Atg7 in intestinal epithelial cells inhibits the formation of pre-cancerous lesions resulting from Apc loss by enhancing immunosurveillance. The antibody-mediated depletion of CD8+ T cells demonstrated a critical role for CD8+ T cells in antitumoral responses resulting from the inhibition of autophagy. We used a broad-spectrum antibiotics treatment to show that the expansion of IFN-producing CD8+ T cells following the deletion of Atg7 is dependent on the intestinal microbiota and is associated with Paneth and goblet cell defects. In addition, the inhibition of autophagy affected tumor cell growth and restrained cancer growth for extended time periods. We demonstrate that the inhibition of autophagy in Apc tumor cells results in a stress response accompanied by metabolic defects, characterized by AMPK activation and p53 cell cycle arrest. This study suggests that autophagy inhibitors may suppress tumorigenesis in patients at high risk of developing colorectal cancer
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Pérez, lanzón María. "Modeling Hormone Receptor Positive Breast Cancer in Immunocompetent Mice Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression Organoids for Modeling Genetic Diseases. In: International Review of Cell and Molecular Biology A preclinical mouse model of osteosarcoma to define the extracellular vesicle-mediated communication between tumor and mesenchymal stem cells Failure of immunosurveillance accelerates aging The metabolomic signature of extreme longevity: Naked mole rats versus mice Lurbinectedin synergizes with immune checkpoint blockade to generate anticancer immunity Laminin-binding integrins are essential for the maintenance of functional mammary secretory epithelium in lactation Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer". Thesis, université Paris-Saclay, 2021. http://www.theses.fr/2021UPASL019.
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Les progrès de la recherche sur le cancer du sein dépendent de la disponibilité d’outils appropriés, comme les lignées cellulaires qui peuvent être implantées chez des souris immunocompétentes. La souche de souris C57Bl/6 est la plus étudiée et c’est la seule pour laquelle certaines variantes génétiques sont disponibles. Étant donné qu'aucune lignée cellulaire de carcinome mammaire à récepteurs hormonaux positifs de souche C57Bl/6 n'est disponible, nous avons décidé d'établir des lignées cellulaires de ce type. Nous avons induit des cancers du sein chez des souris C57BL/6 femelles en utilisant un analogue synthétique de la progestérone combiné à un agent endommageant l'ADN. Des lignées cellulaires ont été établies à partir de ces tumeurs et sélectionnées pour leur positivité au niveau du double récepteur (estrogène + progestérone), ainsi que pour leur transplantabilité chez les femelles C57BL/6. Parmi plusieurs lignées, une lignée cellulaire, que nous avons appelée MD5, remplissait ces critères et a permis l'établissement de tumeurs mal différenciées et très prolifératives. Ces tumeurs ont réduit leur croissance (sans toutefois régresser) lors du traitement par des antagonistes des récepteurs d’œstrogènes, ainsi que par une chimiothérapie à base d'anthracylines. Cependant, ce dernier effet n'a pas été influencé par la déplétion des lymphocytes T et, en outre, ces tumeurs n'ont pas répondu au blocage de PD-1, ce qui suggère que les tumeurs MD5 sont immunologiquement froides. En conclusion, les cellules MD5, dérivées des animaux C57BL/6, constituent un modèle de cancer du sein à récepteurs hormonaux positifs de mauvais pronosticProgress in breast cancer research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best explored mouse strain, C57Bl/6, is also the only one for which multiple genetic variants are available. Driven by the fact that no hormone receptor-positive C57Bl/6-derived mammary carcinoma cell lines are available, we decided to establish such cell lines. Breast cancers were induced in female C57BL/6 mice using a synthetic progesterone analogue combined with a DNA damaging agent. Cell lines were established from these tumors and selected for dual (estrogen + progesterone) receptor positivity, as well as transplantability into C57BL/6 females. One cell line, which we called MD5,fulfilled these criteria and allowed for the establishment of poorly differentiated, highly proliferative, immune cold tumors. Such tumors reduced their growth (though did not regress) upon treatment with estrogen receptor antagonists, as well as with anthracyline-based chemotherapy. However, the latter effect was not influenced by T cell depletion and MD tumors failed to respond to PD-1 blockade, suggesting that they are immunologically cold. In conclusion, C57BL/6-derived MD5 cells constitute a model of poor prognosis hormone receptor-positive breast cancer
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Azour, Halima. "Etude et réalisation d'un nouveau concept de dépistage rapide d'anticorps anti-érythrocytaires et élaboration d'un nouveau mode de titrage d'anticorps anti-érythrocytaires utilisables dans la surveillance des immunisations fœto-maternelles". Bordeaux 2, 1997. http://www.theses.fr/1997BOR28551.
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Pittari, Gianfranco. "NK Cell Tolerance of Self-Specific Apecific Activating Receptor KIR2DS1 in Individuals with Cognate HLA-C2 Ligand". Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T043.
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Les cellules tueuses naturelles (NK) sont régulées par des récepteurs activateurs et inhibiteurs. La plupart des récepteurs inhibiteurs reconnaisse des molécules du complexe majeur d'histocompatibilité (CMH) de classe I, et protège les cellules saines des phénomènes d'auto-immunité médiés par les cellules NK. Cependant, certains récepteurs activateurs, incluant le récepteur killer cell Ig-like receptor (KIR) 2DS1, reconnaissent aussi des ligands CMH de classe I. Cela pose la question de savoir comment les cellules NK qui expriment des récepteurs activateurs deviennent tolérantes au soi. Nous avons cherché à déterminer si la présence de HLA-C2, le ligand du récepteurs 2DS1, peut induire les cellules NK qui expriment le 2DS1 à développer un état de tolérance au soi. Indépendamment de la présence ou de l'absence du ligand HLA-C2 dans le donneur, une activité anti-HLA-C2 a été identifiée in vitro dans certains clones NK 2DS1-positifs. La fréquence des clones NK avec réactivité anti-HLA-C2 était élevée parmi les donneurs homozygotes pour HLA-C1. De façon étonnante, nous n'avons pas constaté de différence statistiquement significative dans la fréquence de cytotoxicité anti-HLA-C2 entre les donneurs HLA-C2 hétérozygotes et les donneurs sans ligand HLA-C2. Par contre, les donneurs HLA-C2 homozygotes montrent une fréquence réduite de clones NK avec réactivité anti-HLA-C2 par rapport aux autres donneurs. Clones 2DS1-positifs qui co-expriment des KIR inhibiteurs spécifiques des molécules HLA de classe I du soi n’étaient pas communément cytotoxiques, et la cytotoxicité anti-HLA-C2 était limité presque exclusivement à des clones positifs seulement pour 2DS1 (« single positive » 2DS1 clones). Nous avons aussi identifié des clones 2DS1 « single positive » avec réactivité anti-HLA-C2 dans des patients recevant une greffe de cellules souches hématopoïétiques à partir de donneurs 2DS1. Ces résultats montrent que plusieurs cellules NK avec réactivité anti-HLA-C2 sont présentes dans des donneurs 2DS1 soit hétérozygotes soit homozygotes pour HLA-C1. En revanche, les clones 2DS1-positifs obtenus par des donneurs homozygotes pour HLA-C2 sont fréquemment tolérants aux antigènes HLA-C2NK cells are regulated by inhibiting and activating cell surface receptors. Most inhibitory receptors recognize MHC-class I antigens, and protect healthy cells from NK cell-mediated auto-aggression. However, certain activating receptors, including the human killer cell Ig-like receptor (KIR) 2DS1, also recognize MHC-class I. This raises the question of how NK cells expressing such activating receptors are tolerized to host tissues. We investigated whether the presence of HLA-C2, the cognate ligand for 2DS1, induces tolerance in 2DS1-expressing NK cells. Anti-HLA-C2 activity could be detected in vitro in some 2DS1 positive NK clones irrespective of presence or absence of HLA-C2 ligand in the donor. The frequency of anti-HLA-C2 reactivity was high in donors homozygous for HLA-C1. Surprisingly, there was no significant difference in frequency of anti-HLA-C2 cytotoxicity in donors heterozygous for HLA-C2 and donors without HLA-C2 ligand. However, donors homozygous for HLA-C2 had significantly reduced frequency of anti-HLA-C2 reactive clones as compared to all other donors. 2DS1 positive clones that express inhibitory KIR for self-HLA class I were commonly non-cytotoxic, and anti-HLA-C2 cytotoxicity was nearly exclusively restricted to 2DS1 single positive clones lacking inhibitory KIR. 2DS1 single positive NK clones with anti-HLA-C2 reactivity were also present post-transplantation in HLA-C2 positive recipients of hematopoietic stem cell transplants from 2DS1 positive donors. These results demonstrate that many NK cells with anti-HLA-C2 reactivity are present in HLA-C1 homozygous and heterozygous donors with 2DS1. In contrast, 2DS1 positive clones from HLA-C2 homozygous donors are frequently tolerant to HLA-C2
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Aarab-Terrisse, Safae. "Impact de l'axe microbiome-thymus sur l'efficacité de la déprivation androgénique et sur le renforcement de l’immuno-surveillance dans le cancer de la prostate Immunodynamics of Explanted Human Tumors for Precision and Personalized Immuno-Oncology Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients". Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL025.
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La déprivation androgénique est la pierre angulaire du traitement du cancer de la prostate (CaP), mais la plupart des patients deviendront réfractaires à la castration (CRPC). En outre, les immunothérapies par inhibiteurs de points de contrôle immunitaire ne sont pour l’instant pas un standard dans la prise en charge de ce cancer en raison de son environnement immunosuppresseur. Notre hypothèse est que pour accroître la sensibilité des patients aux traitements immuno-modulateurs (déprivation androgénique, inhibiteurs des points de contrôle immunitaire et autres), il faudrait restaurer l’environnement immunitaire systémique de l’hôte, et rétablir ainsi un microenvironnement intra-tumoral immuno-reactif de manière plus précoce dans la prise en charge de la maladie.Étant donné que les patients atteints d'un cancer avancé peuvent présenter une dysbiose intestinale, qu’on sait que la composition du microbiote intestinal joue un rôle essentiel dans le succès de tout traitement immuno-modulateur, nous avons donc analysé l'impact du système immunitaire, de la composition du microbiote intestinal et la relation entre les deux composants sur la durée de l’hormono-sensibilité chez les patients atteints de CaP et dans un modèle murin de cancer de la prostate (Lignées Myc-CaP).Tout d'abord, en utilisant des anticorps depletant les lymphocytes CD4 ou CD8 et des souris nudes- athymiques, nous avons démontré le rôle clé des lymphocytes T dans le temps jusqu’à résistance à la castration. Ensuite, à l'aide d'expériences d'antibiotiques à large spectre, de « cohousing », de transplantation microbienne fécale (FMT) et d’utilisation de probiotiques immunogènes nous avons dévoilé le rôle fondamental du microbiote intestinal de l’hôte dans le contrôle de la croissance des tumeurs pendant la suppression androgénique. Troisièmement, la métagénomique des fèces couplées aux analyses métabolomiques sanguines ont mis en évidence des changements significatifs associés à la castration et aux manipulations du microbiote. Enfin, l’intégrité du thymus semble être compromise par la présence du cancer de la prostate, que la castration ne restaure pas. Néanmoins, un microbiote sain restaurerait la thymopoïèse et l'émigration des lymphocytes matures associés à une immunosurveillance anticancéreuse efficace. Dans l'ensemble, nous démontrons que la déprivation androgénique permet d'obtenir une efficacité anti-cancéreuse optimale et de longue durée, de manière dépendante des lymphocytes T lorsque la dysbiose intestinale est compensée par la FMT d’individus sains ou par des probiotiques immunogènes. Par ailleurs ce renforcement du tonus immunitaire de l’hôte permettrait de sensibiliser le cancer de la prostate aux traitements ultérieurs par immunothérapieAndrogen deprivation therapy (ADT) is the backbone treatment for Prostate cancer (PCa), but most patients will become refractory to castration (CRPC). In addition, immune checkpoint blockade may not be an option for CRPC. Given that advanced cancer patients may exhibit a gut dysbiosis and the pivotal role of the intestinal microbiota composition in dictating the success of chemo-and immuno-therapy, we analyzed the role of the immune system, the impact of the gut microbiota and the inter-relationship between both components in the time to CRPC in PCa patients and in a mouse model of prostate cancer (MyC-CaP cell line). First, using CD4 or CD8 depleting antibodies and athymic nude mice, we demonstrated the key role of T lymphocytes in the time to progression during ADT. Secondly, using cohousing experiments, fecal microbial transplantation and broad spectrum antibiotics, we unveiled the seminal role of the host microbiota in governing tumor growth control during ADT. Third, metagenomics coupled with metabolomics analyses highlighted significant changes associated with ADT, their physiological relevance being currently investigated. Finally, while the development of PCa compromises the thymus integrity despite ADT; healthy microbiota restores thymopoiesis and the emigration of mature lymphocytes associated with effective anticancer immunosurveillance. Altogether, ADT mediates a full blown T cell-dependent anti-PCa cancer efficacy when intestinal dysbiosis is compensated by FMT or immunogenic probiotics
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Chen, Yung Che y 陳永哲. "Investigating the role of epigenetic change-mediated compromised immune surveillance in lung disease". Thesis, 2015. http://ndltd.ncl.edu.tw/handle/24945375796033288877.
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博士長庚大學
臨床醫學研究所
103
The purpose of this thesis research is to investigate epigenetic changes-mediated compromised immune surveillance that may affect the development of two common lung diseases, pulmonary tuberculosis (TB) and lung cancer. Both diseases develop when the individual’s immune system can not execute its normal function to eradicate either M.tb or tumor cell. Epigenetic changes, such as DNA methylation, play an essential role in regulating immune responses and gene expressions to environmental stimuli, such as hypoxia, toxin, and infection. Thus, we sough to identify epigenetic biomarkers for early diagnoses and predicting outcomes of both lung diseases. In the first part of this study, we found initially that one genetic haplotype (-16934A/-15607G/-196 to -174 insertion /1350T) of the toll-lke receptor 2 (TLR2) gene was linked to the susceptibility to active pulmonary TB disease in a cohort of 184 patients with pulmonary TB and 184 healthy controls, using direct sequencing. TB patients with the 1350 CC genotype, homozygous short alleles for GT repeats, or -196 to -174 deletion/deletion had higher blood natural killer (NK) cell counts. Then, we found higher DNA methylation levels over five CpG sites (3, 7, 9, 13, and 18) of the TLR2 promoter region, lower TLR2 gene expression, lower TLR2 protein expression on blood monocyte, higher TLR2 proein expression on blood NK cell, and higher serum TNF-α/IFN-γ levels in another cohort of 99 sputum culture positive pulmonary TB patients as compared to that in 77 healthy subjects, using pyrosequencing, RT-PCR, flowcytometry, and ELISA methods. Most of these biomarkers were reversed to normal after 6-month anti-TB treatment. In the second part, we initially analyzed whole genome microarray gene expression profiles of peripheral blood mononuclear cells from 30 patients with newly-diagnosed advanced stage non-small cell lung cancer (NSCLC), and 20 age-, sex-, and co-morbidity-matched healthy controls.We found the IL4 pathway significantly enriched in both tumor progression and chemotherapy signatures in patients with advanced NSCLC. Quantitative RT-PCR for the four up-regulated (S100A15, DOK2) and down-regulated (TLR7, TOP1MT) genes in the patients, and the six upregulated (TLR7, CRISP3, TOP1MT) and down-regulated (S100A15, DOK2, IL2RG) genes after chemotherapy confirmed the validity of the microarray results. Immunohistochemical analysis of the paraffin-embedded lung cancer tissues identified strong S100A15 nuclear staining not only in stage IV NSCLC as compared to stage IIIB NSCLC, but also in patients with stable or progressive disease as compared to those with a partial response. Then, we try to correlate aberrant DNA methylation patterns of the S100A15 promoter region with distant metastasis of lung adenocarcinoma. Taken together, results of this thesis research allow a better understanding of the effect of compromised immune surveillance on the development, diagnoses, and outcomes of both lung diseses through epigenetic regulations.
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Cunningham, Thomas D. "Estrogen inducible Proteinase Inhibitor 9 protects target cells from immune surveillance and apoptosis /". 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3337746.
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Thesis (Ph. D.)--University of Illinois at Urbana-Champaign, 2008.Source: Dissertation Abstracts International, Volume: 69-11, Section: B, page: 6768. Adviser: David J. Shapiro. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.
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Witalis, Mariko. "Immune mechanisms controlling angioimmunoblastic T cell lymphoma progression". Thesis, 2020. http://hdl.handle.net/1866/25274.
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Le lymphome angioimmunoblastique à cellules T (AITL) est un lymphome périphérique à cellules T agressif dont les symptômes sont la lymphadénopathie et l'hypergammaglobulinémie. Actuellement, les patients atteints du AITL ont des options de thérapeutiques limitées et des résultats cliniques défavorables, avec un taux de survie sur 5 ans d'environ 30%. Les cellules tumorales du AITL proviennent de cellules T CD4+ appelées cellules T auxiliaires folliculaires (Tfh). Les cellules Tfh sont essentielles dans le centre germinatif (GC), où elles facilitent l'expansion et la différentiation des cellules B en plasmocytes. Cette fonction d'aide est soutenue par de nombreuses protéines dérivées des cellules Tfh et des programmes de transcription qui pourraient aussi fonctionner dans les cellules tumorales du AITL. Par conséquent, la perturbation des principaux mécanismes de signalisation soutenant l'identité des cellules Tfh et leurs interactions avec les cellules B pourrait inhiber la croissance du AITL. Des études ont démontré que les cellules hyperactives de type Tfh provoquent une accumulation de cellules immunitaires telles que les cellules B, les plasmocytes et les macrophages dans les tumeurs.
Cependant, le microenvironnement du AITL n'a pas été bien étudié et il n'a pas été vérifié si certaines cellules immunitaires pourraient être utilisées pour arrêter la croissance de la tumeur. Bien que l’on trouve des cellules Tfh circulantes dans l’AITL humain, le taux de propagation peut varier d’un patient à l’autre. Ainsi, une possibilité est la présence de mécanismes de surveillance immunitaire s'opposant à la progression de la tumeur. En accord avec cette hypothèse, un signal positif pour la phagocytose nommé SLAMF7 (contrebalancé par la voie inhibitrice CD47-SIRPα) est exprimé dans un sous-ensemble de patients atteints du AITL. Toutefois, la corrélation entre les différents niveaux d'expression du SLAMF7 et l'amélioration des résultats pour les patients n'a pas été étudiée.
En utilisant des souris Roquinsan/+, qui développent spontanément l’AITL, nous avons étudié le rôle des mécanismes de signalisation immunitaire dans les cellules tumorales de type Tfh et du microenvironnement tumoral. Nous avons cherché à inhiber les protéines et les voies de signalisation typiques des cellules Tfh dans les tumeurs afin d'évaluer la valeur thérapeutique potentielle. Nous avons aussi étudié le rôle de la phagocytose dépendante des macrophages dans le contexte SLAMF7 et comment la modulation de la signalisation de CD47-SIRPα peut améliorer l'efficacité de la phagocytose des cellules tumorales. Notre hypothèse centrale est qu'en supprimant les programmes fondamentaux des cellules Tfh ou en favorisant l'élimination phagocytaire des cellules tumorales de type Tfh, nous pouvons favoriser la régression de la tumeur.
Nous avons démontré que les tumeurs AITL nécessitent des protéines d’identité des cellules Tfh essentielles telles que le facteur de transcription Bcl6 et la protéine adaptatrice SAP, ainsi que la communication entre les cellules T et B (T-B). Même en l'absence de GC classiques, les cellules tumorales de type Tfh ont apporté un soutien aux cellules B. Cela est démontré par des titres élevés d'IgG et l'accumulation de cellules précurseurs des plasmocytes dans les tumeurs. Nous avons trouvé des preuves de l'opposition entre la surveillance immunitaire et l'évasion au sein des tumeurs de type AITL, car les cellules Tfh augmentent l’expression de la molécule inhibitrice CD47 tandis que les macrophages stimulent le niveau de SLAMF7. Les cellules de type AITL ont été phagocytées plus efficacement in vitro quand la signalisation du CD47 était bloquée. En résumé, nous démontrons que les voies de signalisation importantes pour l'identité des cellules Tfh et la communication entre les cellules T et B sont essentielles pour la progression de l’AITL et suggèrent qu’une surveillance immunitaire continue par les macrophages peut influencer l’évolution de la maladie. Des études futures pourraient explorer la possibilité de combiner des inhibiteurs de l'activité des cellules Tfh ou T-B avec des médicaments qui stimulent l'activité phagocytaire antitumorale pour améliorer l'efficacité thérapeutique du traitement.Angioimmunoblastic T cell lymphoma (AITL) is an aggressive peripheral T cell lymphoma manifesting with symptoms such as generalized lymphadenopathy and hypergammaglobulinemia. Currently, AITL patients have limited treatment options and poor clinical outcomes with a 5-year survival rate around 30%. AITL tumor cells derive from a subset of CD4+ T cell, the T follicular helper (Tfh) cell. Tfh cells are essential in germinal centers (GC), where they facilitate B cell expansion and differentiation into plasma cells. This helper function is supported by numerous Tfh cell-derived proteins and transcriptional programs which may still be operational in AITL tumor cells. Therefore, disrupting key signaling mechanisms sustaining Tfh cell identity and their ability to interact with B cells could inhibit AITL tumor growth. Studies have demonstrated that these hyperactive Tfh-like cells lead to the accumulation of immune cell subsets such as B cells, plasma cells, and macrophages within tumor lymph nodes. Nevertheless, the AITL tumor microenvironment itself has not been well-studied and whether some immune cells could be harnessed to impede tumor growth has not been tested. In human AITL, although circulating Tfh cells have been reported, the rate of tumor spreading can vary between patients. As such, one possibility is the presence of immune surveillance mechanisms opposing tumor progression. In line with this idea, SLAMF7, a positive signal for macrophage-mediated phagocytosis (counterbalanced by the inhibitory CD47-SIRPα pathway), is expressed in a subset of AITL patients. Despite this, whether differing levels of SLAMF7 expression correlates with improved patient outcomes has not been investigated. Using Roquinsan/+ mice, a spontaneous AITL-like mouse model, we addressed the role of immune signaling mechanisms within Tfh-like tumor cells and the surrounding tumor microenvironment that would promote tumor regression. First, we aimed to inhibit signature Tfh cell proteins and downstream signaling pathways in developed AITL-like tumors to evaluate potential therapeutic value. Second, we investigated the role of macrophage-mediated phagocytosis in the context of SLAMF7 and how modulating CD47-SIRPα signaling may enhance the efficiency of AITL tumor cell engulfment. Our central hypothesis is that by removing fundamental Tfh cell supporting programs from tumor cells or by promoting the phagocytic removal of Tfh-like tumor cells we can favour tumor regression and impair future growth. Through this work, we demonstrated that AITL-like tumors continuously require critical Tfh cell identity proteins such as transcription factor Bcl6 and adaptor protein SAP, as well as T cell-B cell (T-B) crosstalk. Importantly, despite the absence of conventional GCs, Tfh-like tumor cells provided functional support to B cells as evidenced by elevated IgG titers and accumulation of plasma cell precursors in tumors. We also found evidence of opposition between immune surveillance and evasion within AITL-like tumors as Tfh-like cells upregulated inhibitory CD47 levels while macrophages increased expression of prophagocytic SLAMF7. Moreover, AITL-like tumor cells were more efficiently phagocytosed in vitro when CD47 signaling was blocked. Taken together, we demonstrate that pathways important for Tfh cell identity and T-B communication are critical for AITL-like disease progression and suggest that ongoing macrophage-mediated immune surveillance may influence disease outcomes. Future studies may explore combining inhibitors of Tfh cell activity or T-B crosstalk along with drugs which boost antitumor phagocytic activity to further improve the therapeutic efficacy of treatment.
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Baschuk, Nikola [Verfasser]. "Immune surveillance of cancer : molecular and translational aspects of cytotoxic effector : target cell interactions / vorgelegt von Nikola Baschuk". 2009. http://d-nb.info/998592005/34.
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CHEN, LI-TING y 陳立亭. "To Investigate the Effect of T cell Specific Transgenic Blimp-1 Expression on Immune Surveillance of Glioma-Bearing Mice". Thesis, 2016. http://ndltd.ncl.edu.tw/handle/dd2hs4.
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碩士國防醫學院
微生物及免疫學研究所
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Glioblastoma multiforme (GBM) is kind of glioma, it’s also the most common primary central nervous system malignant tumor. Standard treatment includes surgical resection, chemo-therapy combine radiation therapy. However, previous research indicated that GBM grow fast and is highly invasive. Despite standard treatment, the median survival of GBM patients is less than 16 months. For these reasons, the present study focuses on gene therapy and immunotherapy for GBM. Immune system plays an important role on eliminating abnormal cells (e.g., over-proliferated cells). However, the immune cells are deregulated in GBM. Previous researches have indicated that GBM leads to immune suppression by downregulation of Type I T helper cells and upregulation of Treg cells. B lymphocyte-induced maturation protein-1 (Blimp-1), which is important for T cell maturation, can enhance Treg cells function, suppress Th1 cells and impede Th17 cells. In our study, we established orthotropic syngeneic brain tumor model on T cell specific Blimp-1 transgenic mice to investigate the effect of T cell specific transgenic Blimp-1 expression on immune surveillance of glioma-bearing mice. The results show that the tumor growth rate was faster in Blimp-1 transgenic mice compared with wild type mice. T cell population is decreased, and the Treg cell population is increased in brain of glioma-bearing Blimp-1 transgenic mice. These results suggest Blimp-1 is important for immune surveillance in glioma.
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Enzler, Thomas [Verfasser]. "GM-CSF and IFN-γ [IFN-gamma] deficiency link autoimmune diseases and cancer : a cancer immune surveillance controversy / of Thomas Enzler". 2004. http://d-nb.info/971611033/34.
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Aulwurm, Steffen Alexander [Verfasser]. "Aktivierung der angeborenen und adaptiven Immunantwort und deren Bedeutung bei der Immunantwort gegenüber malignen Gliomen = Activation of the innate and adaptive immune response and its role in the immune surveillance of malignant glioma / vorgelegt von Steffen Alexander Aulwurm". 2005. http://d-nb.info/974850012/34.
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Wischhusen, Jörg Hinrich [Verfasser]. "Apoptoseresistenz und Vermeidung von Anti-Tumor-Immunität -zwei verwandte (?) Überlebensstrategien maligner Gliomzellen = Resistance to apoptosis and escape from host immune surveillance - two related (?) survival mechanisms of malignant glioma cells / vorgelegt von Jörg Hinrich Wischhusen". 2004. http://d-nb.info/972522425/34.
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Chang, Chun-Jung y 張峻榮. "Evasion of fibrotic lung myofibroblasts from IFN-γ immuno-surveillance". Thesis, 2019. http://ndltd.ncl.edu.tw/handle/7ygg7j.
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Dessureault, Mireille. "Effet du sécrétome des cellules sénescentes sur la réponse inflammatoire orchestrée par les macrophages". Thèse, 2016. http://hdl.handle.net/1866/18640.
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L’élimination des cellules sénescentes met en jeu le SASP et les cellules immunitaires de l’immunité innée et adaptative tels que les macrophages (Mφ). Dans le cadre de ce projet, nous rapportons que le SASP a un effet pléiotropique sur l’activité des cellules immunitaires incluant leur recrutement, leur activation et leur différenciation. Nos données montrent que les Mφ humains mis en culture avec le SASP de fibroblastes humains développement un profil inflammatoire spécifique au SASP caractérisé par une sécrétion pro-inflammatoire (M1) (ex : IL- 1β, GM-CSF) et des marqueurs de surface anti-inflammatoires (M2) (cellules CD23+CD206+). Le SASP est aussi capable d’augmenter les capacités d’invasion des Mφ, tel que montré via des essais d’invasion, mais n’a pas d’effet sur la différentiation des monocytes. Nos modèles de co- culture montrent que, quoique les cellules NK sont probablement responsables de l’élimination directe et spécifique des cellules sénescentes, leur activité peut être modulée par d’autres cellules immunitaires tels que les Mφ qui réduisent l’élimination faite par les cellules NK, suggérant un profil M2. Les lymphocytes T CD8+ sont aussi essentiels pour l’élimination des cellules sénescentes puisque leur retrait retarde le processus. De plus, nous démontrons que les cellules T CD4+ mises en culture pendant 48h dans le SASP sécrètent de hauts niveaux d’IL-4, indiquant une polarisation Th2. Somme toute, ces données montrent que le SASP peut moduler l’activité des Mφ tout comme celle d’autres cellules immunitaires impliquées dans l’élimination des cellules sénescentes et peut promouvoir, étonnamment, une réponse immunosuppressive pouvant être importante pendant la réparation tissulaire.Senescent cell clearance brings into play the senescence-associated secretory phenotype (SASP) and immune cells from the innate and adaptive immunity including macrophages (Mφ). In this study, we report that the SASP has a pleiotropic effect on immune cell activity including recruitment, activation and differentiation. We show that human Mφ exposed to the SASP of human fibroblasts develop a SASP-specific inflammatory profile characterized by pro- inflammatory (M1) secretion (e.g. IL-1β, GM-CSF) and anti-inflammatory (M2) surface markers (CD23 and CD206). The SASP also increases Mφ invasion but has no effect on monocyte differentiation. Co-culture models show that while NK cells are likely the direct effectors of senescent cell specific killing, their activity is modulated by other immune cells including Mφ, which reduced NK-mediated killing, suggesting a M2 profile. Alternatively, CD8+ T lymphocytes are essential for senescent cell killing by NK cells. Finally, CD4+ T cells cultured for 48h in the SASP secrete high-levels of IL-4, indicating a Th2 polarization. Overall, our data reveal that the SASP can modulate Mφ and other immune cells involved in senescent cell clearance and surprisingly promote an immunosuppressive response that could be important in tissue repair.