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Dissertations / Theses on the topic 'Immunology; Tumour cells'
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1
Dearman, Rebecca Jane. "Antibody-dependent destruction of neoplastic cells by celluar effectors." Thesis, University of Southampton, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.276345.
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McDonnell, Alison. "The role of dendritic cells in the cross-presentation of tumour antigens." University of Western Australia. School of Medicine and Pharmacology, 2009. http://theses.library.uwa.edu.au/adt-WU2010.0017.
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[Truncated abstract] A paradox exists in tumour immunology whereby progressive tumour growth exists in parallel with an anti-tumour T cell response. This defective T cell response is thought to result from the induction of T cell tolerance and/or tumour induced immunosuppression, which act to inhibit the activation, differentiation and function of tumour-specific CD8+ T cells. Dendritic cells (DCs) are professional antigen presenting cells (APCs) that are critical to the generation of effective CTL; however their function and phenotype is often defective or altered in tumour-bearing hosts, which may limit their capacity to mount an effective tumour specific T cell response. In this thesis, the role of DCs in the cross-presentation of tumour antigen was assessed in terms of their APC function, migration and location. In doing so the intention was to gain insight into the early processes that potentially contribute to the development of an ineffective anti-tumour immune response. This study examined cross-presentation of the nominal tumour antigen, influenza A hemagglutinin (HA) expressed by the murine malignant mesothelioma cell line, AB1-HA. Cross-presentation was predominantly restricted to the local draining lymph nodes throughout tumour growth and was mediated by CD8a+ and CD8a- DCs. This results in an ineffective CTL response due to the lack of DC activation and the presence of potentially immunosuppressive B7 molecules. However, the capacity of the CD8a- DC subset to cross-present antigen suggested a role for migratory tumour-resident DCs in this process. Analysis of tumour infiltrating DCs showed that they were paralysed in their capacity to cross-present tumour antigen and were immobilised at the tumour site. Conversely, cross-presentation of tumour antigen in the local draining lymph node was dependent on the continuous traffic of antigen from the tumour microenvironment. In this vein, small numbers of metastatic tumour cells were detected in the draining lymph nodes, however their isolation was dependent on the removal of DCs and T cells, suggesting immune control of metastatic spread. Thus, tumour cells may be the source of antigen for cross-presentation by DCs in the tumour draining lymph nodes. .... In conclusion, the results presented in this thesis support a role for DCs in the generation of tumour-specific T cell responses that fail to control tumour growth. In addition the results provide a basis for further investigation into the effects of chemotherapy on the source and form of tumour antigen for cross-presentation by specific DC subsets in the tumour bearing host. These findings may have important implications for the development of future anti-cancer immune therapies targeting DCs.
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Ajzensztejn, Daniel. "Harnessing the immune system to reject cancers through genetic modifications of tumour cells." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:1aafa1f4-ee10-4081-b621-d81b9979d96a.
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The immune system, which defends the body against a wide array of threats, is gaining a growing role in the fight against cancer. For an immunotherapy to be successful, it needs to overcome intrinsically weak tumour-specific immune responses. There are two broad approaches to achieving this goal: targeting the various arms of the immune system or targeting the cancer and its microenvironment. The experiments discussed in this thesis adopt the second approach. Tumours were transduced with a combination of costimulatory molecules: CD48, CD54, CD70 & CD86, the chemokine CX3CL1 and the cytokines: IFNγ, GM-CSF and IL-12. Transduction of costimulatory molecules enhances priming in-vitro and cause tumour rejection and delayed tumour growth in-vivo. This effect is demonstrated with single costimulatory molecules but is more pronounced when multiple costimulatory molecules are transduced. Addition of the cytokines and chemokine enhanced tumour rejection, and also resulted in partial rejection of contralateral parental tumours. Attempts to enhance anti-tumour memory by fusing IL-2 and IL-15 to their respective receptors are also discussed. Work in a human/mouse chimeric PD-1 mouse model shows that transduction of multiple costimulatory molecules is able to overcome intrinsic anti-PD-1 resistance. Radiation is known to result in upregulation of several costimulatory molecules within tumours or their infiltrating dendritic cells. The experiments presented here suggest that radiation therapy may be useful in overcoming anti-PD-1 therapy resistance. In human trials, approximately three quarters of cancers fail to respond to anti-PD-1 therapies. Understanding and potentially overcoming anti-PD-1 therapy resistance is therefore of great interest.
4
Windebank, Kevin. "Early signal transduction events during activation of the cytolytic process in human natural killer cells." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337563.
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Pullyblank, Anne Maria. "Evaluation of the role of monoclonal antibodies m17-1A, c17-1A and cSF25 in antibody-dependent cell-mediated cytotoxicity and an exploration of the possible mechanisms of action." Thesis, Imperial College London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268015.
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Petrovic, Kristina. "Exploring the therapeutic potential of CAR-engineered T-cells targeting endothelial markers on tumour and inflamed vasculature." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8468/.
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T-cells engineered to target tumour antigens through surface-expressed chimeric antigen receptors (CARs) are highly effective in treating some leukaemias. The challenge is to extend this success to solid tumours. Tumour endothelial marker 8 (TEM8) is a conserved transmembrane protein overexpressed on the vasculature of many solid tumours but low or undetectable on healthy tissues, making it a potential CAR T -cell target. This thesis explores the safety and therapeutic efficacy of this approach by generating five human TEM8-specific CARs, expressing them in T-lymphocytes, and characterising their functional responses to TEM8 in vitro. Four of the five CARs showed unexpected reactivity to control cells, and in mouse studies some of these proved toxic while most were selectively lost from the circulation, an effect that was TEM8-dependent. Only one CAR selectively responded to target cells overexpressing human TEM8 in vitro but was unable to recognise mouse TEM8, so further in vivo studies were not possible. These results highlight the sensitivity and potency of CAR -engineered T -cells and demonstrate the need for additional safety measures if targeting TEM8. The thesis also demonstrates that another TEM, CLEC14A, is overexpressed in some inflammatory liver diseases, and identifies a suitable mouse model for exploring the therapeutic potential ofCLEC14A-specific CAR-expressing regulatory T-cells.
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Nirmal, Ajit Johnson. "Deconvolution of the immune landscape of cancer transcriptomics data, its relationship to patient survival and tumour subtypes." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31519.
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The immune response to a given cancer can profoundly influence a tumour's trajectory and response to treatment, but the ability to analyse this component of the microenvironment is still limited. To this end, a number of immune marker gene signatures have been reported which were designed to enable the profiling of the immune system from transcriptomics data from tissue and blood samples. Our initial analyses of these resources suggested that these existing signatures had a number of serious deficiencies. In this study, a co-expression based approach led to the development of a new set of immune cell marker gene signatures (ImSig). ImSig supports the quantitative and qualitative assessment of eight immune cell types in expression data generated from either blood or tissue. The utility of ImSig was validated across a wide variety of clinical datasets and compared to published signatures. Evidence is provided for the superiority of ImSig and the utility of network analysis for data deconvolution, demonstrating the ability to monitor changes in immune cell abundance and activation state. ImSig was also used to examine immune infiltration in the context of cancer classification and treatment. Patient-matched ER+ breast cancer samples before and after treatment with letrozole were analysed. Significant elevation of infiltration of macrophages and T cells on treatment was observed in responders but not in non-responders, potentially revealing a biomarker for response. ImSig was also used to study the immune infiltrate in 12 cancer types. By computing the relative abundance of immune cells in these samples, their relationship to survival was investigated. It was interesting to observe that half of the cancers showed trends towards poor prognosis with increased infiltration of immune cells. ImSig alongside the network-based framework can also be used for a more explorative analysis such as to identify biomarkers and activation or differentiation states of immune cells. Melanoma is a highly immunogenic cancer and has shown tremendous success with immune checkpoint inhibitors in a subset of patients. In chapter-6, the molecular subgrouping of melanoma was explored using a network-based approach. Despite the plethora of evidence suggesting various aspects of the immune system to contribute towards the response to immunotherapy in melanoma, there has been little to no effort to consider this heterogeneity while developing molecular subgroups. The use of ImSig was therefore explored for the stratification of melanoma patients into immuno-subgroups. The subgrouping methodology divided the tumours into four groups with different immune profiles. Interestingly, these groupings showed prognostic significance, reiterating the need to consider the heterogeneity of immune cells in future studies. On identifying the most dominant phenotypes that contribute towards prognosis of these patients and in comparison to the published subgroupings of melanoma, we argue that the subgroup of samples enriched in keratin genes are not clinically meaningful. ImSig and the associated analysis framework described in this work, support the retrospective analysis of tissue derived transcriptomics data enabling better characterisation of immune infiltrate associated with disease, and in so doing, provide a resource useful for prognosis and potentially in guiding treatment.
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Chong, Tsung Wen. "Targeting the hypoxic tumour phenotype with specific T-cell immunotherapy." Thesis, University of Oxford, 2004. http://ora.ox.ac.uk/objects/uuid:d22f1d74-44eb-4560-9249-f6127accd1b1.
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Sugiyarto, Gessa. "Characterising the preferential suppression of potent anti-tumour CTL responses by regulatory T cells." Thesis, University of Southampton, 2014. https://eprints.soton.ac.uk/379016/.
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Li, Ka-Kit. "The role of CD8+ regulatory T cells in anti-tumour immune responses in hepatocellular carcinoma." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/7940/.
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Tumour specific effector T-cells can be detected in the blood and tumours of patients with hepatocellular carcinoma (HCC) but fail to mount effective immune responses. Attempts to amplify anti-tumour immune responses using immunotherapy show promise, but are hampered by the presence of suppressive regulatory T-cells (Treg) that inhibit anti-tumour immune responses. Many different subsets of Treg have since been identified including regulatory T-cells expressing the surface marker CD8 (CD8⁺Treg). A set of experiments was designed in an attempt to increase our understanding on how CD8⁺Treg may disrupt anti-tumour response and by what mechanisms they are induced. CD8⁺Treg was analysed by isolation of liver-derived T-cells from human HCC. Monocyte-derived dendritic cells (moDC) matured with tumour tissue conditioned medium were used to assess they potential to induce CD8⁺Treg. CD8⁺Treg infiltrating HCC demonstrated a suppressive phenotype. The co-culture of naïve CD8⁺T-cells with tumour-conditioned moDC induces a population of CD8⁺Treg through an IDO dependent mechanism. This population of induced T-cells was able to suppress via the CD39-adenosine pathway. The findings of the mechanisms involved in the induction of CD8⁺Treg by DC and the involvement of CD39 in the suppressive capacity of these novel T-cells, may guide the development of future immunotherapeutic in HCC.
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Balathasan, Lukxmi. "Characterising the role of circulating immune cells in brain metastasis." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:e7620d30-7e4a-468b-b819-db4cf27eaef6.
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Brain metastasis is a frequent occurrence in cancer patients and carries a high mortality rate. The incidence of brain metastasis is on the rise, highlighting the need for improved therapeutic intervention. Immune cells have been shown to promote disseminated tumour cells to colonise the lung and liver. Therefore, we aim to determine whether immune cells also facilitate brain metastasis by describing the host immune response to tumour cells attached to the brain vasculature. We developed a model of brain metastasis by using ultrasound guidance to perform intracardiac injection of tumour cells. Using this method, we identified highly and weakly brain metastatic cell lines. To understand how cancer cells develop into brain metastases, we analysed brains harvested 4 h- 14 d after tumour injections. At 4 h after intracardiac injection, only cell lines that developed into brain metastases were found adhered to the brain vasculature in high numbers. A small number of arrested tumour cells clustered with CD45⁺ immune cells. These tumour-CD45 clusters persisted over time whilst the frequency of solitary tumour cells declined. Tumour-associated CD45⁺ immune cells were identified to be Ly6G⁺Gr-1⁺CD11c⁻ myeloid cells. Considerably more tumour-CD45⁺ immune cell clusters were found within the brain vasculature when tumour cells were injected into mice bearing a primary tumour. Increased tumour-CD45⁺ immune cells clusters correlated with an increased number of brain metastases in the same group of mice. We also found a positive association between increased tumour-immune clusters and levels of tumour and host derived G-CSF. To establish a causal relationship between tumour cell-CD45 clusters and metastases, we developed an experimental setup for transcranial imaging. Our results suggest that tumour recruited immune cells may promote tumour cell colonisation of the brain and provides a framework for further investigation.
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Ananth, Abhirami. "Surgical Stress Attenuates Pre-existing Anti-tumour Immunity Resulting in Postoperative Metastases and local Recurrence in a Murine Model." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31697.
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Solid malignancies in cancer patients require surgical intervention; however, surgery has been shown to promote the metastatic potential of tumour cells. Surgery-induced impairment of adaptive immunity is poorly understood, thus, our aim is to characterize the impact of surgery on tumour antigen-specific cytotoxic T lymphocyte function. To generate anti-tumour immunity, we adopted a C57/B6 model of B16 melanoma immunized with intramuscular (IM) AdhDCT, an adenovirus expressing the melanoma-associated antigen human dopachrome tautomerase (hDCT). Surgical stress was induced by left abdominal nephrectomy. We found that surgery reduces overall survival in AdhDCT-immunized mice, whereas those that did not undergo surgery were cured of their tumours. Surgical stress also decreases both the proportion and absolute spleen numbers of DCT-specific IFN-gamma+ CD8+ T-cells by over 2-fold. We have shown that perioperative suppression of antigen-specific T-cells can lead to increased tumour burden in a murine melanoma model.
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Jain, Jayati. "Engineering antibodies to study and improve immunomagnetic isolation of tumour cells." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:81355801-b331-4705-bfef-204a29ee0347.
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Cell separation based on antibody-targeted magnetic beads has been widely used in a number of applications in immunology, microbiology, oncology and more recently, in the isolation of circulating tumour cells (CTCs) in cancer patients. Although other cell separation techniques such as size based cell filtration and Fluorescence Activated Cell Sorting have also been in popular use, immunomagnetic cell isolation possesses the advantages of high throughput, good specificity and reduced cell stress. However, certain fundamental features of the cell-bead interface are still unknown. In this study, some of the key features of the cell-bead synapse were investigated in an effort to improve the efficiency of immunomagnetic cell isolation and reduce its dependence on high expressing cell surface markers. A clinically relevant antibody fragment (Fab) against tyrosine kinase receptor HER2 was applied to study the immunomagnetic isolation of HER2 expressing cancer cells. First, the minimum number of target proteins required on a cell for it to be isolated was determined. Second, the importance of the primary antibody affinity was investigated, using a series of Fab mutants with known kinetics and it was shown that despite starting with sub-nanomolar affinity, improving Fab affinity increased cell isolation. Third, the influence of the connection between the primary antibody and the bead was studied by comparing Fab bridged to the magnetic bead via a secondary antibody, Protein L or streptavidin; the high affinity biotin-streptavidin linkage increased isolation sensitivity by an order of magnitude. Fourth, the effect of manipulating cytoskeletal polymerization and cell membrane fluidity using small molecules was tested; cholesterol depletion decreased isolation and cholesterol loading increased cell isolation. The insights from these observations were then applied to isolate a panel of cell lines expressing a wide range of surface HER2. While the standard approach isolated less than 10% of low HER2 expressing cancer cells from spiked rabbit and human blood, our enhanced approach with the optimized cholesterol level, antibody affinity and antibody-bead linkage could specifically isolate more than 80% of such cells. The final part of this work focussed on developing an antibody clamp that could physically restrict the antigen within its binding site on the Fab and prevent antigen dissociation, using the HER2-Fab complex and the anti-myc peptide antibody 9E10. Work from this thesis provides useful insights into the molecular and cellular parameters guiding immunomagnetic cell isolation and can be used to extend the range of target receptors and biomarkers for tumour cell isolation and other types of cell separation, thereby enhancing the power and capacity of this approach.
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Vallius, Laura I. "Modulating the immune system by amino acid depletion : IDO and beyond." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:eb1a1987-4121-4042-be82-2aafb67c9941.
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Amino acid availability plays an important role in modulating the activity of T-cells. One of the pathways employed by T-cells to sense nutrient levels is the “mammalian target of rapamycin” (mTOR) pathway that is inhibited in response to nutrient depletion. Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme along the tryptophan catabolising kynurenine pathway. T-cells are very sensitive to lack of this essential amino acid in their microenvironment and this confers strong immunomodulatory properties to cells expressing active IDO. It therefore has a significant physiological role as a homeostatic mechanism used in mammalian organisms to dampen excessive activation of the immune system but is also used as an immune evasion mechanism by many cancers. In this study, we investigated the IDO inhibitory properties and mechanism of action of the tryptophan metabolite 3-hydroxyanthranilic acid (3-HAA) that potentially forms a negative feedback loop in the kynurenine pathway. We studied the molecule in enzymatic assays, in live cells and discovered that it inhibits IDO in an indirect way via the formation of hydrogen peroxide. Secondly, we looked at the effects of tryptophan and its metabolites on T-cell proliferation and mTOR activity, and discovered a metabolite that inhibits T-cell proliferation. Lastly we examined mechanisms of T-cell suppression employed by myeloid derived suppressor cells (MDSCs), focusing on their ability to deplete amino acids from their microenvironment. We were able to exclude tryptophan consumption as a suppressive mechanism and established that by manipulating extracellular concentrations of several amino acids other than arginine and cysteine – that are known to be utilised by MDSCs - we were able to reduce their inhibitory properties. In summary, we have described in detail how 3-HAA inhibits IDO in in vitro assays, outlined how some tryptophan metabolites can inhibit T-cell proliferation, and clarified aspects of suppressive mechanism employed by MDSCs.
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Mundy-Bosse, Bethany L. "Myeloid-Derived Suppressor Cells in Tumor Immunology." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1311261626.
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Murray, Nicholas. "Costimulation of T cells and its role in T cell recognition of malignant colorectal cells in vitro." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301247.
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Karydis, Ioannis. "The role of tryptophan and the mTOR pathway in T cell fate determination." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:1831d28b-52cb-47ee-8047-f6044cd10301.
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The adaptive immune response forms an essential part of the cancer immuno-editing process, whereby nascent malignant cells are detected and destroyed prior to forming tumours. The process is tightly controlled to minimise collateral damage to healthy tissue. One of the mechanisms evolved for this purpose and frequently co-opted by malignant cells is the creation of a microenvironment scarce in essential amino-acids through the use of catabolic enzymes such as Indoleamine 2,3-dioxygenase (IDO) , responsible for the rate-limiting step in tryptophan catabolism. The evolutionary conserved GCN2 and mTORC1 pathways respond to amino-acid starvation by triggering emergency homeostatic response programmes that aim to conserve nutrients by shutting down biosynthetic pathways, slowing cell cycle progression and facilitating autophagy. This research project focuses on elucidating the interaction between IDO activity and these pathways and its implications for the immune-editing process. The role of the mTOR kinase as a regulator of T cell fate following exposure to cognate antigen has recently become apparent. Experiments described herein confirm that in murine and human models of T cell activation exposure to tryptophan starvation results in significant mTORC1 inhibition and a modified phenotype with reduced Tbet expression, altered cytokine secretion profile, greatly impaired proliferative capability and expanded CD4+ FoxP3+ CD25high subpopulations. Additional results confirmed that the action of IDO is sufficient to deplete tryptophan from the microenvironment to levels sufficient to depress the mTORC1 axis and trigger GCN2 activity even in tumour cell lines. Lower extracellular tryptophan levels were necessary to perturb these pathways In IDO expressing cell lines, suggesting that compensatory mechanisms allow continued proliferation of malignant cells in the face of conditions that severely impede an anti-cancer immune response. In conclusion, manipulation of the mTORC1 axis via IDO-induced tryptophan depletion is an important tumour immune-escape mechanism that can be a target for cancer immunotherapies.
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Bell, Mary Siobhan. "Malignancy antigens of the Erlich ascites cell." Thesis, Queen's University Belfast, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317049.
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Carlsten, Mattias. "Molecular specificities of NK cell-mediated recognition of human tumor cells." Stockholm, 2010. http://diss.kib.ki.se/2010/978-91-7409-686-6/.
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Khan, Sarwat Tahsin. "An Interleukin-12-Expressing Oncolytic-Virus Infected Autologous Tumor Cell Vaccine Generates Potent Anti-Tumor Immune Responses." Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37940.
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Cachia, Philip Greville. "Studies of idiotope expression in B-cell chronic lymphocytic leukaemia." Thesis, University of Edinburgh, 1989. http://hdl.handle.net/1842/23764.
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Popple, Amy Lee. "The tumour microenvironment influences antigen specific T cell transmigration." Thesis, University of Nottingham, 2012. http://eprints.nottingham.ac.uk/12584/.
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T cell infiltration into tumours is essential for tumour antigen recognition and tumour cell elimination. The aim of this study was to develop a better understanding of T cell infiltration into tumours, focusing on two opposing arms of an immune response, anti-tumour CD8 Tcells and Regulatory T cells (Tregs). Activated CD4 T helper cells are also of importance but could not be studied due to the time constraints of the project. The effect of T cell signalling at the immunological synapse following interactions between T cells and APCs presenting cognate antigen have been well studied [1]. The endothelium is neither a stereotypical APC nor simply a passive filter barrier for non-cognate infiltrating T cells. The endothelium can activel influence the development of an inflammatory response depending on the functional state of both the endothelium and interacting T cells (resting versus recently activated T cells)and the type of interactions (cognate versus non-cognate). The hypothesis was that recognition of antigens presented in the context of major histocompatibility complex (MHC)molecules by endothelium aids T cell transmigration and hence infiltration into tissues, including into tumours. In this study, the data highlights that high avidity TRP-2 specific CD8 T cell transmigration across murine lung endothelium requires recognition of TRP-2 peptide presented by the endothelium, aiding recruitment of antigen-specific T cells into tissues in the absence of endothelial cell killing. In order for antigen specific T cells to migrate into the tumour, the tumour endothelium therefore needs to present tumour antigens. In addition to CD8 T cells, high numbers of Tregs have been found within tumours but the key mediators for this recruitment remain uncertain. The data shows a novel mechanism for Treg transmigration where cognate antigen-specific recognition of self-peptides was required for transmigration with preferential transmigration of Tregs across syngeneic rather than allogeneic endothelium. Upregulation of major histocompatibility complex (MHC) class II and adhesion molecules, by IFN-γ and TNF-α, together with a gradient of the tumour associated chemokine CXCL12 were also pre-requisites for efficient Treg transmigration. Previous studies have shown that high CXCL12 expression can induce fugetaxis of tumour cells leading to efficient metastatic spread and a poor prognosis. These results would suggest that low levels of CXCL12 and recognition of self peptides presented by self MHC on endothelial cells allows efficient migration of Tregs whereas higher levels of CXCL12 may promote tumour metastases and lead to fugetaxis of the Tregs leading to an even worse prognosis. In conclusion recognition of cognate antigen presented by endothelium enhances antigenspecific transmigration of CD8 and Regulatory T cells. This study therefore reports a novel mechanism for T cell subset infiltration into tumours where high avidity CD8 T cells require recognition of cognate tumour antigen presented on tumour endothelium in the context of MHC class I and conversely regulatory T cell infiltration into tumours depends on the repertoire of self-peptides presented on tumour endothelium in the context of MHC class II. Alteration of antigen presentation or MHC expression on tumour endothelium therefore represents a mechanism whereby T cell infiltration can be altered to re-direct anti-tumour immune responses.
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Zhang, Tong. "Novel approaches to identify T cell-recognized tumor antigens and to redirect T cells for adoptive immunotherapy." Diss., The University of Arizona, 2003. http://hdl.handle.net/10150/280461.
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Tumor antigens (Ags) and adoptive immunotherapy are two important topics in tumor immunology. Traditional methods for identifying T cell-recognized tumor antigens and adoptive therapy using antigen-specific T cells are laborious and difficult. Rapid developments in molecular biology and immunology have allowed us to design novel strategies to achieve these two goals more efficiently. A novel strategy, SING (S̲I̲gnal transduction molecule-mediated, N̲FAT-controlled, G̲FP expression), for cloning T-cell recognized tumor Ags, was designed using Ag-specific T cells. The SING system is an artificial Ag presentation system, in which a mouse T cell line BW5147 has been manipulated to respond to stimulation by Ag-specific TCR (the resultant BW5147 cells are named BS cells). Either Ag peptide-pulsed or Ag-expressing BS cells could become transiently fluorescent (GFP⁺) and puromycin resistant after TCR engagement. In combination with retrovirally mediated functional genomics, the SING strategy should allow us to isolate antigen-expressing (GFP⁺) cells directly and retrieve sequences coding for tumor antigens by PCR amplification of genomic DNA from GFP⁺ BS cells. To investigate whether three-domain single chain T cell receptors (3D-scTCR) are able to redirect T cells to recognize tumor cells, multiple scTCR constructs were constructed and retrovirally transduced into T cells. The effects of CD8, CD28 and the complete CD3 complex on scTCR-induced T cell activation were also determined. Compared with full-length TCR (flTCR)-modified T cells and native CTLs, seTCR-modified T cells had high thresholds for response to Ag stimulation. After adoptive transfer of TCR (either scTCR or flTCR)-modified T cells into tumor-bearing mice, the in vivo tumor growth was controlled to some extent, although most TCR-modified T cell recipient mice didn't show significant signs of anti-tumor effects. This result suggests the possible application of scTCR- as well as fITCR-modified T cells for adoptive immunotherapy. Finally, to accomplish the above goals, we systematically investigated the optimal conditions for transduction of murine primary T cells as well as T cell lines. Our results showed that successful infection of murine primary T cells required a combination of high titer (>10⁷ CFU/ml) of ecotropic retroviral vectors and proper timing of infection (within 24 hours after mitogen stimulation).
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Franchini, Fanny. "Immune regulatory networks in inflammation-driven cancer." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:2314081e-8c3f-43c7-9ea6-edf43430a43c.
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The incidence of colorectal cancer (CRC) is increasing and the prognosis for patients with advanced or metastatic disease is relatively poor. Immunotherapies hold great promise, but deploying them effectively in CRC patients will require further knowledge of the complex cellular and molecular interactions that occur between intestinal tumours and the host immune system. The objective of this study is to understand the mechanisms by which lack of immune cell regulation in the gut can drive the formation of colon adenocarcinomas. In addition, this work aims to identify new mechanisms involved in progression to metastatic disease. Using mouse model systems, we found that aberrant activity of Treg cells deficient in IL-10 can promote inflammation-driven CRC. IL-10 deficient Tregs have increased capacity to drive tumourigenesis compared to their CD4+ effector T cell counterparts. RNA sequencing revealed specific upregulation of several genes, including a newly-described cytokine, in tumour-promoting Tregs. We explored cytokine regulation and the tumour microenvironment, and show that the inflammatory cytokine IL-6 and TGFÎ2 are necessary for tumour formation in this model. Moreover, disease is associated with a marked stromal cell signature that is induced as a consequence of Treg deficiency in IL-10 production. Gp38+ stromal cells are dominant producers of IL-6, and potent ECM modellers. Furthermore, tumours driven by IL-10 deficient Tregs express high amounts of the pro-mesenchymal transcription factor Sox4. Using combined in vitro and in vivo analyses, we confirm that Sox4 is involved in tumour growth and characterise its expression in CRC patients. Collectively, our findings suggest that Tregs and stromal cells act together to foster a microenvironment that promotes disease progression, notably through the expression of Sox4 in tumour cells. These findings open an exciting avenue to explore the phenotype of tumour-promoting Tregs and to study Sox4 function in metastatic disease.
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Montgomery, Anthony. "The targeting of T-helper cells to tumours using PPD-monoclonal antibody heteroconjugates." Thesis, University of Cambridge, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385716.
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Ybarrondo, Ana-Belen. "Regulation of tumor necrosis factor and interferon-gamma release from lymphokine-activated killer cells." Diss., The University of Arizona, 1990. http://hdl.handle.net/10150/185298.
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Peripheral blood lymphocytes cultured in interleukin 2 (IL-2) acquire the ability to lyse tumor cell targets in a non-major histocompatability complex (MHC) restricted manner. These lymphokine activated killer (LAK) cells release tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN-γ) in culture and when stimulated by interaction with tumor cells in vitro. The capacity of several suppressive factors to affect the release of TNF and IFN-γ from LAK cells which have been stimulated with K562 erythroleukemia cells was investigated. A number of agents known to inhibit mononuclear phagocyte secretion of TNF were tested, including prostaglandin E₂ (PGE₂), alpha-globulins and the synthetic protease inhibitor tosyl-arginine methyl ester (TAME). The alpha globulins and TAME are thought to suppress TNF release from monocytes by inhibiting proteolytic cleavage of the cytokine from the cell surface. The addition of PGE₂, whole plasma alpha globulins, purified alpha-1-acid glycoprotein, and TAME inhibited TNF and IFN-γ release in a concentration dependent manner. These inhibitory factors appear to act directly on the lymphocytes to suppress cytokine secretion, as the presence of monocytes or metabolically active tumor cells was not required. The effects of alpha-1-acid glycoprotein on LAK cells were also investigated. The addition of this alpha globulin fraction inhibits the incorporation of ³[H] thymidine by LAK cells stimulated with tumor cells, and results in a detectable decrease in TNF mRNA. The capacity of alpha-1-acid glycoprotein to suppress the release of TNF production also resulted in an inhibition of LAK cell generation which was reversed by the addition of exogenous TNF. In contrast to their suppressive effect on peripheral blood monocytes, the protease inhibitors alpha-1-antitrypsin and alpha-2-macroglobulin enhanced TNF secretion from LAK cells exposed to leukemia cells. Analysis of cell surface TNF expression by fluorescence activated cell sorting (FACS) suggest that the observed differences in regulation reflect the capacity of particular phenotypes to express TNF as a transmembrane molecule. The data presented here indicate that the regulation of TNF release by LAK cells stimulated with tumor cells differs significantly from that previously observed in monocytes and suggest a regulatory role for alpha-1-acid glycoprotein in TNF secretion by LAK cells.
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Rongcun, Yang. "The HER2/neu oncoprotein and dendritic cells in immunity against tumors /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4052-5/.
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Baloche, Valentin. "Contributions négatives et positives de la galectine-9 au développement tumoral : étude dans des modèles tumoraux murins syngéniques In the MB49 Murine Model, Genetic Ablation of Galectin-9 Enhances Anti-Tumor Immune Response: Possible Role of a Greater CXCL9/Il-6 Production Tumor Exosomal Micrornas Thwarting Anti-Tumor Immune Responses in Nasopharyngeal Carcinomas Interferon β and Anti-PD1/PD-L1 Checkpoint Blockade Cooperate in NK Cell-Mediated Killing of Nasopharyngeal Carcinoma Cells Interferon Beta Increases NK Cell Cytotoxicity against Tumor Cells in Patients with Nasopharyngeal Carcinoma via Tumor Necrosis Factor Apoptosis-Inducing Ligand Emerging Therapeutic Targets for Nasopharyngeal Carcinoma: Opportunities and Challenges Galectin-9 Promotes a Suppressive Microenvironment in Human Cancer by Enhancing STING Degradation." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS117.
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Comme les autres galectines, la galectine-9(gal-9) est une lectine animale qui interagit avec un sous-groupe défini de polysaccharides portés par des glycoprotéines ou des glycolipides. La gal-9 associée aux cellules exerce de multiples fonctions dans le cytoplasme, dans le noyau et à la surface de la membrane plasmique. Quelques publications suggèrent que la gal-9 intra-cellulaire inhibe la mobilité des cellules malignes et exerce un effet antimétastatique. En outre la gal-9 peut être sécrétée dans le milieu extra-cellulaire où elle se comporte comme une cytokine avec des effets principalement immunosuppresseurs. Ces effets ont été mis en évidence dans un contexte tumoral chez l’homme et dans des modèles murins. Cependant, on ne disposait pas jusqu’à présent d’un modèle tumoral murin permettant d’évaluer les effets pro-tumoraux ou antitumoraux de la gal-9 indépendamment de la gal-9 des cellules infiltrantes. Pour résoudre ce problème, nous avons dérivé, en employant la technologie CRISPR/Cas9, des clones isogéniques invalidés ou non pour la gal-9 à partir de 2 lignées tumorales murines : CT26 (fond génétique BALB/c) et MB49 (fond génétique C57BL/6). Dans le cas de la lignée MB49, nous avons pu mettre en évidence un phénotype remarquable in vivo. Lors de transplantations itératives, on assiste pour les tumeurs dérivées des clones invalidées à une réduction drastique de la croissance tumorale au bout de 3 ou 4 passages sur les souris syngéniques mais pas sur les souris immunodéficientes. L’émergence de la réponse immunitaire responsable de cet arrêt de la croissance tumorale a été étudiée par immunohistochimie, dosage de cytokines en multiplex dans les extraits tumoraux et analyse du transtriptome par RNAseq. L’augmentation de la production intra-tumorale d’interféron-γ, de CXCL9 et d’Il-6 semble jouer un rôle important dans le renforcement de la réponse immunitaire contre les tumeurs KO-gal-9Like other galectins, galectin-9 (gal-9) is an animal lectin which interacts with a defined subgroup of glycans carried by glycoproteins or glycolipids. Gal-9 associated with cells performs multiple functions in the cytoplasm, in the nucleus and at the surface of the plasma membrane. Some publications suggest that intracellular gal-9 inhibits the mobility of malignant cells and exerts an anti-metastatic effect. In addition, gal-9 can be secreted into the extracellular medium where it behaves like a cytokine with mainly immunosuppressive effects. These effects have been demonstrated in the context of human tumors and in mouse tumor models. However, so far there was no murine tumor model available to assess the pro-tumor or anti-tumor effet of gal-9 independently of gal-9 produced by infiltrating cells. To address this issue, we derived isogenic clones invalidated or not for gal-9 from 2 murine tumoral lines : CT26 (BABL/c genetic background) and MB49 (C57BL/6 genetic background), using CRISPR/Cas9 technology. In the case of the MB49 line, we were able to demonstrate a remarkable phenotype in vivo. During serial transplantations, we saw, for tumors derived from invalidated clones, a dramatic reduction in tumor growth after 3 or 4 passages in syngenic mice but not in immunodeficient mice. The emergence of the immune response responsible for this arrest of tumor growth was investigated by immunohistochemistry, multiplex cytokine assay in tumor extracts and transcriptome analysis by RNAseq. Increased intra-tumor production of interferon-γ, CXCL9 and Il-6 appears to play an important role in enhancing the immune response against KO-gal-9 tumors
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Blazquez, Roman Juan Luis. "Role of the BTN3A family of proteins in the recognition mechanism of tumor cells by gamma delta-T cells : characterization of physical and functional interactions goberning BTN3A biology." Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0194.
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Chez la plupart des primates adultes, les lymphocytes Vγ9Vδ2 représentant la majorité des LT γδ circulants, jouent un rôle fondamentale dans l’immunité anti-infectieuse et anti-tumorale grâce à sa capacité d’identifier l’accumulation pathologique des phosphoantigènes dans les cellules infectées/ transformées. Dans ce contexte, les molécules BTN3A (glycoprotéines membranaires) ont été identifiées comme les médiateurs principaux impliqués dans l’activation des cellules Vγ9Vδ2 induite par les phosphoantigènes.Les travaux développés durant la thèse visent à étudier, grâce à la méthode CRIPSR-Cas9, l’importance relative de chaque paralogue de BTN3A (BTN3A1, BTN3A2, BTN3A3) dans l’activation des cellules γδ. Nous avons ensuite approfondi la façon dont les molécules BTN3A interagissent dans les cellules tumorales afin d’activer les lymphocytes Vγ9Vδ2 grâce aux méthodes de Co-IP, FRET et PLA. En parallèle, nous avons finalement mis en évidence la surexpression des molécules BTN3A dans les cellules tumorales après stimulation avec l’IFNγ. En outre, on a pu montrer que la stimulation des cellules tumorales avec l’IFNγ induit une meilleure activation des lymphocytes Vγ9Vδ2 contre ses cibles. Enfin, l’ensemble de ces travaux a permis d’approfondir la caractérisation fonctionnelle des protéines BTN3A exprimées dans les cellules cibles afin d’activer les lymphocytes Vγ9Vδ2. En plus, ces travaux ont aussi approfondi dans les interactions entre les différents membres de la famille des protéines BTN3A, avec ou sans phosphoantigènesIn most primates, peripheral blood Vγ9Vδ2-T cells are known to play a major role in anti-infectious and anti-tumor immunity thanks to their capacity to identify small pyrophosphate molecules termed phosphoantigens (PAg), which tend to accumulate in transformed/infected cells. In this regard, BTN3A molecules (membrane glycoproteins) were identified as key mediators of Vγ9Vδ2-T cells activation induced by phosphoantigens.The main body of this thesis aims to decipher, by gene-deletion approaches (CRISPR-Cas9), the relative relevance of each BTN3A paralogue (BTN3A1, BTN3A2 and BTN3A3) in the activation of Vγ9Vδ2-T cells, upon phosphoantigens’ intracellular accumulation. Hereafter, we have deepen in the way BTN3A proteins interact between each other in tumor cells to activate Vγ9Vδ2-T cells by Co-IP and FRET. Last but not least, we also demonstrate that IFNγ is involved in the regulation of BTN3A expression and, in addition, we evidence that IFNγ stimulation of tumor cells improves the activation of Vγ9Vδ2-T cells against their targets.To sum up, the set of works performed during the thesis provide new insights about BTN3A proteins’ functional and physical interactions required to fully activate Vγ9Vδ2-T cells, in absence or presence of phosphoantigens
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Oldham, Kimberley Anne. "The recruitment and role of effector and regulatory T cells in renal cell carcinoma." Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3263/.
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Immunotherapy for renal cell carcinoma (RCC) has yielded some clinical responses. However this approach frequently fails, possibly due to inefficient migration of T-cells to tumour tissue or immunosuppressive mechanisms within the tumour environment. To aid development of T-cell therapy for RCC I investigated how T-cells are recruited to this tumour, which T-cell subsets infiltrate, and how they function. Analysis of the expression of all 19 chemokine receptors on matched TIL and PBMC demonstrated that CCR5, CXCR3 and CXCR6 were expressed at significantly higher levels on tumour-infiltrating T-cells than memory T-cells in PBMC, suggesting a role for these receptors in recruitment to RCC. Immunohistochemistry showed the corresponding ligands were present in RCC, and transwell assays confirmed the ligands induce migration of TIL. I demonstrated Foxp3\(^+\)CD25\(^{hi}\)CD127\(^{low}\) Tregs were enriched within the tumour, and also expressed high levels of CCR5, CXCR3 and CXCR6, as well as CCR6. They lacked expression of IL-2 and IFN-\(\gamma\) post-stimulation, consistent with a regulatory phenotype. Functional characterisation of Foxp3\(^-\) TIL demonstrated they can function ex vivo, however their high expression of the inhibitory molecule PD-1 may indicate exhaustion in vivo. Double positive CD4\(^+\)CD8\(^+\) T-cells were also enriched in TIL and had a similar functional profile to CD8 T-cells.
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Ko, Jennifer S. "Mechanism of Myeloid-Derived Suppressor Cell Accumulation in Cancer and Susceptibility to Reversal by Sunitinib." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1259869673.
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Maggs, Luke. "The role of stem cell graft derived natural killer cells in regulating patient outcomes from allogeneic haematopoietic stem cell transplantation." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8633/.
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Myeloid and lymphoid malignancies are potentially curable through a graft versus leukaemia (GvL) effect following allogeneic haematopoietic stem cell transplantation. Whilst donor T cell are thought to be the main mediators of GvL, the effect of donor NK cells within HLA matched T cell depleted transplant setting is more unclear. Patient blood samples were analysed during the first month post-transplant, with higher reconstitution of NK cells at two weeks conferring a relapse protection association. Donor stem cell graft samples, from which NK cells within the patient at two weeks are thought to be derived, similarly displayed a strong association between high NK cell dose and protection from disease relapse. CD56dimDNAM+ NK cells were found to be the population with the most significant association. The ability of NK cells to kill AML blasts in a DNAM dependent manner was shown indicating that direct killing of residual tumour cells may be a valid mechanism of GvL. These findings suggest that optimising the number of NK cells within stem cell grafts should be considered as a means to prevent disease relapse.
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Ortiz, Myrna Lillian. "Immature Myeloid Cells Promote Tumor Formation Via Non-Suppressive Mechanism." Scholar Commons, 2014. https://scholarcommons.usf.edu/etd/5089.
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ABSTRACT
Although there is ample evidence linking chronic inflammation with cancer, the cellular mechanisms involved in early events leading to tumor development remain unclear. Myeloid cells are an intricate part of inflammation. They consist of mature cells represented by macrophages, dendritic cells and granulocytes and a population of Immature Myeloid Cells (IMC), which in healthy individuals are cells in transition to mature cells. There is a substantial expansion of IMC in cancer and many other pathological conditions which is associated with pathologic activation of these cells. As a result, these cells acquire the ability to suppress immune responses and are termed Myeloid-derived Suppressor Cells (MDSCs). Although the role of MDSC in immune suppression in cancer and tumor progression is well established, their contribution to tumor development is still uncertain. The fact that cells with MDSC phenotype and function are observed in chronic inflammation raised the possibility that these cells can contribute to initial stages of tumor development. To address this question, we used an experimental system where the number of IMC was regulated by the expression of S100A9 protein.
In this project, we used two different models of chronic inflammation in S100A9 transgenic (S100A9tg) and S100A9 knock-out (S100A9KO) mice. In the first model, we created the conditions for topical accumulation of these cells in the skin in the absence of infection or tissue damage using S100A9tg mice. Accumulation of IMC in the skin resulted in a dramatic increase in the formation of skin tumors during epidermal carcinogenesis. Conversely, lack of myeloid cell accumulation in S100A9KO mice substantially reduced the formation of skin papillomas. The effect of IMC was not associated with immune suppression but with the recruitment of CD4+ T cells mediated by CCL4 chemokine released by activated IMC. Elimination of CD4+ T cells or blockade of CCL4 abrogated the increase in tumor formation caused by myeloid cells. Thus, this study implicates the accumulation of IMC as an initial step in facilitating of tumor formation, which can mediate the recruitment of CD4+ T cells via the release of CCL4 chemokine.
In the second model, we used inflammation-associated lung cancer caused by the chemical lung carcinogen urethane in combination with exposure to cigarette smoke referred to throughout as CS. Exposure of mice to CS alone resulted in a significant accumulation of cells with typical MDSC phenotype in different organs; however, these cells lacked immune suppressive activity and could not be defined as bona fide MDSC. When CS was combined with the single dose of urethane, it led to the accumulation of immune suppressive cells. The expansion of MDSC followed the onset of lung tumors development. This suggests that MDSC in this model is not the preceding factor but rather a consequence of tumor formation. Further studies are necessary to determine the relevance of targeting these cells for cancer treatment and prevention.
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Wolpert, Elisabeth Z. "T-lymphocyte mediated killing af TAP-deficient tumor cells and immunodominance of minor histocompatibility antigens /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19980525wolp.
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Sherger, Matthew George. "Identification of Myeloid Derived Suppressor Cells in Tumor Bearing Dogs." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1337617975.
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Meyer, Verena. "Selective analysis of specific HLA ligand repertoires: poxviral CD8+ T cell epitopes and phosphorylated HLA ligands of tumor cells." [S.l. : s.n.], 2008.
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O'Toole, Alison. "Tumour Necrosis Factor-#alpha# signalling : potential roles in the pathophysiology of multiple organ failure." Thesis, University of Bristol, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364934.
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Flament, Héloïse. "Modélisation de la réponse anti-tumorale des lymphocytes T CD4+ à l’aide 1) d’une tumeur transplantée exprimant un antigène de manière inductible et 2) de souris porteuses de tumeurs «spontanées»." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T031.
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Le rôle des lymphocytes T CD4+ dans la progression des tumeurs et dans l'immunité anti-tumorale est de plus en plus reconnu chez l'homme et chez la souris. Les mécanismes effecteurs de l’immunité T CD4+ contre le cancer ont été étudiés principalement dans des systèmes de tumeurs transplantées. Dans ces modèles, de nombreuses cellules tumorales meurent au moment de l'implantation, ce qui conduit à la libération de l'antigène tumoral (Ag) dans un contexte inflammatoire. Ceci contraste avec la croissance lente et non-destructrice des tumeurs humaines aux stades précoces. Nous avons montré que la présentation de l’Ag retreint par le CMH-II DBY, libéré par des cellules tumorales mortes injectées en sous-cutané, peut persister durant plusieurs semaines dans le ganglion drainant. L’activation précoce d’une réponse immune dirigée contre l’Ag lors de l’injection de lignées tumorales peut gêner l’étude des relations entre les tumeurs et le système immunitaire. Par conséquent, nous avons généré une lignée tumorale dans laquelle l’expression de DBY peut être induite in vivo à distance de l’implantation. Nous avons également utilisé un modèle de tumeurs pulmonaires endogènes se développant dans des souris transgéniques KrasG12D, p53flox et exprimant DBY de manière spécifique. Notre objectif était d'étudier dans ces deux modèles l'histoire naturelle de la réponse des lymphocytes T CD4+ spécifiques de la tumeur. Dans le système de tumeur transplantée «Ag inductible », nous avons montré que DBY est présenté de manière efficace à des cellules naïves T CD4+ spécifiques dans les ganglions drainant la tumeur. Les réponses prolifératives et effectrices sont similaires dans les systèmes où DBY est exprimé de façon inductible in vivo ou constitutive. Le récepteur de co-stimulation ICOS, ainsi que les récepteurs co-inhibiteurs PD-1 et BTLA sont régulés positivement sur les lymphocytes T CD4+ spécifiques en réponse à l’Ag. La production de cytokines en réponse à une restimulation in vitro révèle un profil effecteur mixte TH1 /TH17. Notamment, un petit pourcentage de lymphocytes T co-expriment les marqueurs de cytotoxicité LAMP-1 et granzyme B. Ainsi, lorsqu’un Ag apparaît à distance de l'implantation de la tumeur, il n’est pas ignoré et n’induit pas de tolérance immune. D'autres mécanismes doivent être considérés pour expliquer l'absence de rejet de tumeur efficace malgré l’activation et la migration des cellules effectrices T CD4+ dans les tumeurs. Les travaux réalisés sur le modèle de tumeurs pulmonaires endogènes sont en cours. A ce stade, nous avons observé que, comme dans les tumeurs transplantées, l’Ag est présenté aux LT CD4+ naïfs qui prolifèrent dans le ganglion drainant et ne se différencient pas en cellules T régulatrices, même aux stades très avancés de la maladie. La capacité des tumeurs à induire une réponse T effectrice semble liée à leur stade de développement. Durant la phase tumorale précoce, les LT spécifiques de DBY produisent de l’IFN-γ et du granzyme B. En revanche, des LT spécifiques produisant de l'IL-17 sont retrouvés dans les poumons de souris ayant des tumeurs invasives de stade terminal. Bien que l'IL-17 puisse favoriser la progression des tumeurs, y compris dans les modèles induits par l’oncogène KrasG12D, de nouvelles données suggèrent que les cellules effectrices TH17 possèdent un haut degré de plasticité et peuvent présenter une activité anti-tumorale. Notre modèle pourrait être utile pour tester de nouvelles stratégies de ciblage de l’IL-17 dans l'immunothérapie du cancerThe role of CD4+ T cells in both tumor progression and immunity is being increasingly acknowledged in humans and mice. CD4+ T cell immunity against cancer has been mostly studied using murine transplanted tumor systems. In these models, many tumor cells die at the time of surgical implantation, leading to the release of tumor antigen (Ag) in an inflammatory context. This contrasts with the slow and non-destructive growth of early stage human tumors. Here, we show that the presentation of a MHC class II-restricted model (male, DBY) Ag released by dying fibroblastic tumor cells may last more than 3 weeks in the tumor draining lymph node (dLN). This artificial, early and long lasting priming precludes the study of the interactions between the immune system and tumors at the steady state. We therefore generated a cell line that could be induced to efficiently express DBY as a neoAg after implantation. We also took advantage of a previously described mouse model of genetically engineered, KrasG12D p53flox lung adenocarcinoma to generate a “spontaneous” tumor model expressing DBY. Our aim was to study in these two models the natural history of the tumor-specific CD4+ T cell response. In the transplanted tumor system, we show that the Ag reaches the dLNs and is efficiently presented to naïve specific CD4+ T cells. The proliferative and effector responses were similar in the inducible and constitutively expressed Ag tumor systems. The ICOS co-stimulatory receptor, and the PD-1 and BTLA co-inhibitory receptors were upregulated on the Ag specific CD4+ T cells in the dLN. We did not observe de novo induction of tumor-specific regulatory T cells. Finally, the pattern of secreted lymphokines in the dLN, spleen and tumor after in vitro Ag restimulation was similar, with a mixed TH1/TH17 response. Notably, a small percentage of DBY-specific effector T cells also displayed a cytolytic phenotype marked by the co-expression of granzyme B and LAMP-1. Thus, when the neo-Ag appears at distance of tumor implantation, the tumor was not ignored and did not induce tolerance of naïve CD4+ T cells. Other mechanisms have to be thought to explain the absence of tumor rejection despite efficient priming and migration of effector CD4+ T cells into tumors. Similarly to the strong proliferative response mentioned above, the DBY tumor Ag was efficiently presented in LNs draining “spontaneous” lung tumors, and induced activation and proliferation of adoptively transferred naive T cells. After priming they did not convert into Tregs, even in end-stage disease. This work is still ongoing, but preliminary results show that activated DBY-specific T cells from the dLN and the lungs produced IFN-γ and granzyme B during early stages of the disease. In contrast, IL-17 secreting cells were found exclusively in the lungs from mice with late-stages invasive tumors. Although IL-17 may enhance tumor progression, including in models driven by the Kras oncogen, emerging data strongly suggest that TH17 effector cells demonstrate a high grade of plasticity and can display anti tumor activity. Little is known about the antigen specificity of IL-17 production in lung cancer patients, and our model could be useful to test new strategies targeting either positively or negatively tumor Ag-specific TH17 cells in cancer immunotherapy
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Veerasubramanian, Priya. "HLA allogene expression in multiple myeloma cells : possible use as anti-tumor vaccine." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33037.
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Multiple myeloma (MM) is a plasma cell malignancy with a high mortality rate. The current treatment options may prolong survival but none of them are curative. Allogeneic gene therapy is a novel vaccine strategy that can augment anti-tumor immune responses and cause remission in some non-hematologic cancers. Immunogene transfer has been successfully performed in human and murine myeloma cells using viral vectors. We used immuno-magnetic negative selection to purify myeloma cells from bone marrow (BM) specimens. We investigated the possibility of in vitro culture of bone marrow mononuclear cells (BMMC) and myeloma cell enrichments. We used liposomal and adenoviral vectors to transduce myeloma cell lines. We cloned the allogene HLA-B7 into a recombinant adenoviral transfer plasmid and, subsequently, produced a recombinant, HLA-B7-positive, adenoviral vector. We evaluated allogene expression by the adenoviral vector in myeloma cell lines. In three of four BM samples tested, 95--99% purification of primary myeloma cells was achieved. Poor expansion and considerable variability (6--22 days) in the duration of culture of BMMC (two samples) and purified myeloma cells (four samples) was observed. Adenoviral vectors expressing green fluorescent protein (GFP) were highly efficient (70--94%) for transduction of myeloma cell lines. Using the HLA-B7-adenoviral vector, a small population (13%) of HLA-B7-positive myeloma cells (RPMI-8226 cell line) was identified. These observations support the feasibility of creating a myeloma vaccine by transduction of primary human myeloma cells with an allogene.
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Clever, David C. Clever. "T Cell-Intrinsic PHD Proteins Regulate Pulmonary Immunity." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1471868519.
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Vahlne, Gustaf. "Natural killer cell inhibitory and activating receptors : regulatory role in effector functions against normal and tumor cells /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-430-3/.
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Wrightham, M. N. "Immunotherapeutic approaches to B cell neoplasms using monoclonal anti-idiotypes and cellular effector mechanisms." Thesis, University of Southampton, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383269.
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Raitano, Arthur Bartholomew. "Reciprocal modulation of tumor necrosis factor and gamma interferon receptors in human carcinoma cells: Biological significance and mechanisms of action." Diss., The University of Arizona, 1991. http://hdl.handle.net/10150/185483.
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Human recombinant cytokines may have a role in the clinical treatment of pancreatic and colorectal cancers. In the present studies, the growth inhibitory actions of recombinant human tumor necrosis factor (rhTNF) and recombinant human gamma interferon (rhIFN-γ) were examined in several human pancreatic and colorectal carcinoma cell lines in vitro in relation to the expression TNF and IFN-γ receptors. rhTNF and rhIFN-γ exerted significant, but differential, growth inhibitory effects in five of six cell lines examined. All six cell lines exhibited high affinity binding sites for both ¹²⁵I-labeled rhTNF and ¹²⁵I-labeled rhIFN-γ. However, the basal number of binding sites in general did not correlate with the relative growth inhibitory effects induced by either rhTNF or rhIFN-γ. In contrast, in three cell lines in which the cytokines exerted synergistic effects, rhTNF increased by 2-3 fold the number of ¹²⁵I-rhIFN-γ binding sites. Further, in two of these cell lines, rhIFN-γ also upregulated ¹²⁵I-rhTNF binding. As demonstrated by anti-IFN-γ receptor antibody labeling and the use of transcriptional and translational inhibitors, the increase in ¹²⁵I-rhIFN-γ binding by rhTNF was due to enhanced synthesis and expression of IFN-γ receptor protein. Recombinant human lymphotoxin (rhLT), which binds to the TNF receptor, and recombinant human interleukin-1 alpha (rhIL-1), which binds to a distinct receptor and mimicks many of the biological actions of TNF, also increased the expression of IFN-γ receptors. Further, rhIL-1 exerted synergistic growth inhibitory effects with rhIFN-γ. Taken together, these results suggest that the synergistic effects of either TNF/LT or IL-1 and IFN-γ may involve the upregulation of IFN-γ receptors. The mechanisms by which rhTNF and rhIL-1 upregulate IFN-γ receptors are unclear. However, the upregulatory effects of both rhTNF and rhIL-1 were attenuated by the Ca²⁺ ionophore A23187 and the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate, suggesting that the mechanisms involved in IFN-γ receptor upregulation by TNF and IL-1 are negatively modulated by Ca²⁺ and protein kinase C activation. The results of this dissertation suggest that immunotherapy with recombinant cytokines may be useful in that treatment of pancreatic and colorectal cancer in vivo.
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Ruth, Nicola Dawn. "Capturing T-cell receptors : a potential new modality for targeting hepatic tumours and post-transplantational lymphoproliferative disease (PLTD)." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8533/.
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This project sought to identify paediatric tumour-specific phosphopeptide antigens on Post-transplantation lymphoproliferative disease samples (PTLD) and hepatic tumour samples. Tumour-specific T-cells are difficult to maintain in long-term culture, therefore the secondary aim of this project was exploring modalities for capturing T-cell receptor (TCR), important in recognising tumour-specific antigens. This may result in a tumour-specific product. Potential modalities included T-cell hybridomas and Human Induced Pluripotent Stem Cell (hIPSc) technology to immortalise tumour specific T-cells. As a result, we have developed a technology for expanding these and differentiating them into a T-cell of interest with potential for future clinical application in paediatric tumours, using OP9 DL1 mouse feeder cell system to support differentiation of hIPSc towards haemopoietic lineage, demonstrating functionality of the end stage ‘T-cell product’. In summary we have identified a number of novel phosphopeptide antigens in vitro as well as on patient tissues. This information has been used to identify potential T-cell targets and by formation of hIPSc we have established a method for expanding specific T-cell’s in vitro. Using OP9DL1 cells we have also identified a method for differentiating these cells into lymphocyte-like cells with T-cell functionality therefore representing a possible methodology for expanding tumour-specific T-cells for clinical application.
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Lo, Jennifer Alys. "Regulation of the Inflamed Tumor Phenotype in Melanoma Immunotherapy." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493467.
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Immune checkpoint inhibitors targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) pathways can deliver durable anti-tumor effects. However, a major fraction of metastatic cancer patients fail to respond to checkpoint blockade.
Recent studies suggest that efficacy of checkpoint inhibitors is associated with inflammation in the tumor microenvironment. In this thesis, I demonstrate using genetically-defined murine models that sterile melanomas can be converted into inflamed tumors with improved responses to checkpoint blockade via two independent approaches: introduction of neoantigens and a novel combinatorial therapeutic strategy.
In addition to tumor inflammation, genomic studies have identified elevated numbers of neoantigens, mutated proteins that can serve as targets of immune responses, as potential predictors of clinical benefit. The preponderance of UVR-associated somatic mutations in melanoma has been proposed to play a role in mediating responses to immunotherapy, but model systems to study the contribution of such mutations to anti-melanoma immunity have been lacking. In chapter 2, I present a BrafV600E/Pten-/- syngeneic tumor graft murine model in which melanomas bearing numerous non-synonymous UVB-induced mutations were markedly more inflamed and responsive to PD-1 inhibition than matched parental melanomas.
For the treatment of neoantigen-deficient, poorly-inflamed tumors, in chapter 3 I tested the novel combination of imiquimod, ablative fractional photothermolysis (aFP), and checkpoint inhibitors. In anti-PD-1 resistant models of melanoma and pancreatic adenocarcinoma, addition of imiquimod and aFP produced abscopal tumor regressions with long-term survival in 50-60% of cases. Combination therapy stimulated autoimmunity against wildtype tumor-lineage antigens, suggesting that therapeutic strategies which enhance inflammation and responses against self-antigens may bypass a need for neoantigens and produce major regressions of cancers that are currently refractory to checkpoint blockade in the clinic.
In chapter 4 I show that PD-L1 expression is transcriptionally regulated by the melanocyte lineage factor and oncogene microphthalmia-associated transcription factor (MITF). PD-L1 expression is significantly correlated with MITF copy number in patient melanomas and is induced in skin as part of the MITF-dependent tanning response pathway. Our data suggest that loss of PD-L1 predisposes mice to apparent vitiligo after chronic UVR, suggesting that the UVR-MITF-PD-L1 axis represents a melanocyte lineage-specific mechanism of immune tolerance.Medical Sciences
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Elkovich, Andrea J. "The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5792.
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Myeloid Derived Suppressor Cells (MDSC) represent a significant hurdle to cancer immunotherapy because they dampen anti-tumor cytotoxic T cell responses. Previous studies have reported on the myelo-depletive effects of certain chemotherapies. Using guadecitabine, a next-generation DNA methyltransferase inhibitor (DNMTi), we observed significantly reduced tumor burden in the 4T1 murine mammary carcinoma model. Guadecitabine treatment prevents excessive tumor-induced myeloid proliferation and systemic accumulation, and skews remaining MDSCs toward a beneficial antigen-presenting phenotype. Together, this alters the splenic environment to improve T cell activation and interferon-gamma (IFNg) production. Additionally, guadecitabine enhances the therapeutic effect of adoptively transferred antigen-experienced lymphocytes to diminish tumor growth and improve overall survival. Based on these findings, the immune-modulatory effects of guadecitabine can help rescue the anti-tumor immune response and could contribute to the overall effectiveness of current cancer immunotherapies.
Allergies and asthma are common ailments that are on the rise around the world. Mast cells play a direct role in the signs and symptoms characteristic in allergic patients. The family of A Disintegrin And Metalloproteinases (ADAMs) are involved in regulating many cellular processes by cleaving surface receptors, ligands, and signaling molecules. We sought to determine the role of ADAM17 in mast cell activity. In studies using ADAM17-deficient mast cells, percent degranulation and cytokines released by IgE-mediated activation were significantly reduced. Interestingly, ionomycin-activation was unchanged, suggesting ADAM17 may be involved in IgE-mediated mast cell activation upstream of calcium release. Additionally, ADAM17MC-/- mice showed protection from IgE-, but not histamine-, mediated passive systemic anaphylaxis (PSA). The underlying mechanism behind the reduced degranulation occurs through signaling deficiencies downstream of Lyn phosphorylation. Together, the data suggest that ADAM17 is required for proper mast cell signaling through its interaction with the Src family kinase, Lyn.
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Dempster, Holly. "Characterization of the Anti-Tumour Immune Response Following Treatment with an Infected Leukemia Cell Vaccine." Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37165.
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Current treatment methods for Acute Leukemia (AL) only provide temporary therapeutic efficacy as most patients will experience relapse within 2 years following first remission. Our lab has determined that vaccination with autologous cells infected with oncolytic virus MG1 can provide durable cures in a pre-clinical mouse model of AL. However, the mechanism(s) by which the infected cell vaccine (ICV) stimulates T cell dependent anti-tumour immunity and provides protection against tumour growth is unknown. This thesis was aimed to determine 1) what antigen presenting cell populations are activated post ICV immunization and 2) what T cell subsets are important in developing anti-tumour immunity during ICV immunization. My thesis has demonstrated that ICV immunization is more effective at inducing in vivo dendritic cell activation compared to irradiated L1210 cells alone and this activation may be a reason as to why we see improved anti-tumour efficacy in our ICV model. In addition, we have determined that CD4 T cells play an essential anti-leukemic role during ICV immunization and that neutralizing antibody production is a CD4 T cell dependent mechanism. Our data also demonstrates that both CD4 and CD8 T cell populations from ICV immunized mice provide a leukemia-specific anti-tumour immune response. Taken together, this data suggests that CD4 T cells may be acting as helper T cells to aid in the robust activation of leukemia-specific anti-tumour CD8 T cells. Our pre-clinical data characterizing the immune response has improved our understanding of the mechanism(s) which contribute to the efficacy of the ICV and will help provide a rationale framework with which to begin translating this treatment to clinical trials.
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Rosean, Timothy Robert. "The tumor microenvironment is critical for the development of plasma cell neoplasia in mice." Diss., University of Iowa, 2014. https://ir.uiowa.edu/etd/1497.
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Plasma cell neoplasms (PCN), including multiple myeloma, are tumors of terminally differentiated B cells. Despite a significant research effort, and numerous advances in therapy, most tumors of this B cell lineage remain incurable. To this end, understanding factors which are critical for the development of PCN may lead to new avenues for therapy. Interleukin-6 (IL-6) is a pleiotropic, pro-inflammatory cytokine which supports the growth, proliferation, and survival of myeloma cells.
We found that inflammation, and in particular, IL-6 is critical for the development of PCN. In order to determine if tumor microenvironment (TME) or B cell-derived IL-6 was more important in PCN development, we utilized an adoptive transfer system of tumor formation. By adoptively transferring premalignant B cells into recipients, and then providing the B cells with an inflammatory microenvironment through the use of pristane, we were able to generate donor tumors in recipient mice. Utilizing this method, a series of adoptive transfers were performed to determine the primary source of IL-6 in murine PCN development. We discovered that TME-derived IL-6, and not B cell-derived IL-6, is most critical for PCN development.
Furthermore, in studying the lesions in B cell development which lead to tumor formation, we discovered that IL-6 collaborates with the proto-oncogene c-Myc in spontaneous germinal center (GC) formation. The spontaneous GCs were accompanied by a robust follicular T helper cell response. In characterizing the genetic lesions which lead to the GC formation, we discovered that Myc-transgenic mice develop a significant increase in the population of B1a B cells. Furthermore, these B1a B cells infiltrate the spontaneous GCs of double transgenic Myc/IL-6 mice. Lastly, utilizing our adoptive transfer method, we determined that the germinal center response is necessary for the development of PCN in mice.
Lastly, we focused our efforts on another oncogene which collaborates with IL-6, BCL-2. Double transgenic BCL-2/IL-6 mice develop PCN and spontaneous GCs. Of interest however, the adoptive transfer of BCL-2/IL-6 B cells results in tumor formation without the use of pristane. Furthermore, the adoptive transfer recipients develop bone lesions, hind limb paralysis, and a monoclonal gammopathy. This model closely recapitulates many of the pathophysiological features seen in human PCN. This new model promises to be important for future studies into PCN development and treatment.
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Muccioli, Maria. "Characterizing dsRNA-induced inflammation in ovarian cancer cells." Ohio University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1405707670.
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Nandigam, Harika. "Capability of the Tumor Microenvironment to Attract a Precursor of B-cells and Dendritic Cells from Bone Marrow." Ohio University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1307108043.
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