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1
Zunino, Barbara. „Dialogue entre le métabolisme et l’immunité dans le traitement des cancers“. Thesis, Nice, 2014. http://www.theses.fr/2014NICE4113.
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Il est connu depuis de nombreuses années que le métabolisme des cellules cancéreuses diffère de celui des cellules saines. La Restriction Calorique (RC) est connue pour prolonger la durée de vie et pour limiter l’oncogenèse. Ainsi, il a été montré que la RC et ses mimétiques comme le 2-deoxyglucose (2DG) augmentent l’efficacité de la chimiothérapie et peuvent aussi induire une immunité anti-tumorale. J’ai pu montrer qu’en régulant le métabolisme via la restriction calorique (ou des mimétiques) nous pouvions moduler l’expression de la protéine anti-apoptotique Mcl-1. Ainsi nous avons établi in vivo et in vitro que la RC restaure la sensibilité des cellules de lymphome à l’apoptose induite par un inhibiteur de Bcl-2/XL, l’ABT-737. Nous avons aussi établi que ces effets sont indépendants de la protéine p53 et/ou des « protéines BH3-only ». La deuxième partie de mon travail a été d’élucider les mécanismes moléculaires mis en place lors de la Chimiothérapie Hyperthermique Intra péritonéale (CHIP) pouvant expliquer les effets bénéfiques observés chez les patients atteints d’une carcinose péritonéale (CP). Une partie de ces bénéfices sont dus à la mise en place d’une immunité anti-tumorale. En utilisant des modèles in vivo et in vitro j’ai mis en évidence l’implication de la protéine du choc thermique 90 (Hsp90) dans l’effet observé. Ainsi, l’inhibition spécifique de la Hsp90 réverse les effets protecteurs de la CHIP, soulignant l’importance de cette protéine dans notre modèle d’immunité anti-tumoraleThe link between cell metabolism and cancer at the cellular level has long been known. Caloric restriction (CR) is known to prolong lifespan and to protect from cancer incidence. The molecular mechanisms involved in these benefic effects have been evaluated and may offer new opportunities for therapeutic intervention. Moreover, CR and CR-mimetics such as 2-deoxyglucose (2DG) has been shown to enhance chemotherapy efficiency and to induce an anti-cancer immune response. During the period of my PhD I demonstrated how the modulation of metabolism through caloric restriction or through its mimetics could significantly reduce the expression of the anti-apoptotic protein Mcl-1 and sensitize lymphoma-bearing mice to apoptosis induced by a Bcl-2/XL inhibitor, ABT-737. We have demonstrated that CR can control Mcl-1 translation and sensitize cells to ABT-737-induced death regardless of the presence or absence of p53 and/or of the main “BH3-only proteins”. Then, I focused on deciphering the molecular mechanisms allowing the Hyper-thermic Intra-Peritoneal Chemotherapy (HIPEC) to be beneficial to patients suffering from peritoneal carcinomatosis. Part of the protective effect was mediated through the induction of an efficient anti-cancer immune response. Next, I showed the involvement of heat shock proteins 90 (Hsp90) in the observed effect. Indeed, when Hsp90 was blocked we lost the protection induced by the HIPEC-treated cells, therefore underling the role of Hsp90 in this HIPEC-dependent induction of anti-cancer immune response
2
They, Laetitia. „Renforcement des effets immunomodulateurs d’un anticorps monoclonal anti-tumoral : étude des effets potentialisateurs de thérapies combinées et analyse des mécanismes impliqués“. Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT076/document.
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Le mélanome est la forme la plus agressive des cancers de la peau. Si sa prise en charge à des stades précoces est de bon pronostic, l’espérance de vie des patients chute dramatiquement pour les stades métastatiques. Malgré les avancées thérapeutiques spectaculaires récentes, le problème majeur réside dans la résistance aux traitements et la récidive et le défi principal est désormais de tendre vers un contrôle efficace et durable. Les anticorps monoclonaux (AcM) ont la capacité de cibler et éliminer spécifiquement la cellule tumorale tout en recrutant des cellules du système immunitaire, permettant de développer et/ou renforcer l’immunité de l’hôte avec le développement d’une réponse immune anti-tumorale de type vaccinale. Dans un modèle de tumeur solide de mélanome murin après greffe sous-cutanée des cellules B16F10, nous avons étudié le potentiel immunomodulateur de l’AcM TA99 qui cible un antigène de surface TYRP-1 surexprimé dans les mélanocytes tumoraux. Nos résultats montrent qu’environ 30% des souris sont protégées sur le long-terme et présentent une réponse immunitaire humorale et cellulaire mémoire. Par ailleurs, l’analyse de l’infiltrat immunitaire chez les souris qui échappent au traitement par l’AcM TA99 et qui développent une tumeur à plus ou moins long terme, montre une surexpression de PD-1 et Tim3 associée à une perte de fonctionnalité des cellules effectrices au sein de la tumeur. Ce même phénotype a été observé sur des biopsies de patients atteints de mélanome métastatique. Nous montrons aussi dans le cadre de ce travail que, le blocage de l’axe PD1/PD-L1 par inoculation d’un AcM anti-PD1 au moment de l’échappement, potentialise la réponse immunitaire anti-tumorale et entraîne une augmentation de la survie. Cependant, l’absence de régression complète suggère la mise en place d’autres voies immunosuppressives. En effet nous avons observé une surexpression des ectonucleotidases CD39 et CD73 dans le micro-environnement tumoral suggérant l’implication de l’adénosine dans la résistance au traitement de l’AcM TA99 plus l’α-PD-1. Ce résultat ouvre des perspectives intéressantes pour le blocage concomitant la voie de l’adénosine et de l’axe PD1/PD-L1. Une autre stratégie a consisté à améliorer les effets immunomodulateurs précoces de l’AcM TA99 en le combinant avec l’oxaliplatine, chimiothérapie favorisant la mort immunogénique. Bien que les combinaisons thérapeutiques testées dans cette étude montrent des effets in vivo encourageants avec un délai significatif dans la survie globale, aucune augmentation significative de la réponse anti-tumorale sur le long terme n’a pu être observée, suggérant la mise en place d’autres voies immunosuppressives non redondantes ou des stratégies de combinaisons non adaptées. Une analyse dynamique approfondie, tant phénotypique que fonctionnelle, des différents acteurs cellulaires du micro-environnement tumoral sera une étape clé dans la mise en place de combinaisons pertinentes en association avec l’AcM TA99. Ce travail prend d’autant plus d’intérêt qu’un essai clinique de phase I (IMC-20D7S) utilisant le flanvotumab (équivalent humain de l’AcM TA99) réalisé chez 27 patients atteints de mélanome métastatique, montre des effets cliniques intéressants sans effets secondaires sévères, ouvrant la voie au développement de combinaisons thérapeutiques associées à cet AcMMelanoma is the most aggressive form of skin cancer. Although early management is of good prognosis, the survival of patients decrease dramatically for metastatic stages. Despite the recent spectacular therapeutic advances, the major problem lies in resistance to treatment and relapse and the main challenge now is to develop an effective and sustainable control. Monoclonal antibodies (mAbs) have the ability to specifically target and eliminate tumor cells while recruiting cells from the immune system, to develop and / or enhance the immunity of the host with the development of a vaccinal immune response. In a solid tumor model of murine melanoma after subcutaneous transplantation of B16F10 cells, we investigated the immunomodulatory effect of TA99 mAb targeting a TYRP-1 surface antigen overexpressed in tumor melanocytes. Our results showed that about 30% of mice are protected in the long term and have an antitumoral humoral and cellular immune response. Moreover, the analysis of the immune infiltrate in mice that escape to the treatment with TA99 mAb and develop a tumor, shows an overexpression of PD-1 and Tim3 associated with a loss of effector cell functions within the tumor. This same phenotype has been observed in biopsies of patients with metastatic melanoma. Thus, blocking the PD-1 / PDL-1 axis by inoculation of an anti-PD1 mAb at the time of tumor escape potentiates the anti-tumor immune response and results in increased survival. However, the absence of complete regression suggests the establishment of other immunosuppressive pathways. Indeed we have observed an overexpression of CD39 and CD73 ectonucleotidases in the tumor microenvironment suggesting the involvement of adenosine in the resistance mechanisms observed and opening interesting perspectives for the concomitant blocking of this pathway and the PD1 / PDL-1 axis. Another strategy has been to improve the early immunomodulatory effects of TA99 mAb by combining it with oxaliplatin, a chemotherapy that promotes immunogenic death. Although the therapeutic combinations tested in this study showed encouraging in vivo effects with a significant delay in overall survival, no significant increase in the long-term anti-tumor response was observed, suggesting the establishment of other non-redundant immunosuppressive mechanisms or unsuitable combinations strategies. Both phenotypic and functional analysis of the different cellular actors of the tumor microenvironment will be a key step in the implementation of relevant combinations in association with the TA99 mAb. This work is highlighted by a phase I clinical trial (IMC-20D7S) using flanvotumab (human equivalent of mAb TA99) in 27 patients with metastatic melanoma that shows interesting clinical outcome without severe side effects, opening the way for the development of therapeutic combinations associated with this mAb
3
Zunino, Barbara. „Dialogue entre le métabolisme et l’immunité dans le traitement des cancers“. Electronic Thesis or Diss., Nice, 2014. http://www.theses.fr/2014NICE4113.
Der volle Inhalt der QuelleAnnotation:
Il est connu depuis de nombreuses années que le métabolisme des cellules cancéreuses diffère de celui des cellules saines. La Restriction Calorique (RC) est connue pour prolonger la durée de vie et pour limiter l’oncogenèse. Ainsi, il a été montré que la RC et ses mimétiques comme le 2-deoxyglucose (2DG) augmentent l’efficacité de la chimiothérapie et peuvent aussi induire une immunité anti-tumorale. J’ai pu montrer qu’en régulant le métabolisme via la restriction calorique (ou des mimétiques) nous pouvions moduler l’expression de la protéine anti-apoptotique Mcl-1. Ainsi nous avons établi in vivo et in vitro que la RC restaure la sensibilité des cellules de lymphome à l’apoptose induite par un inhibiteur de Bcl-2/XL, l’ABT-737. Nous avons aussi établi que ces effets sont indépendants de la protéine p53 et/ou des « protéines BH3-only ». La deuxième partie de mon travail a été d’élucider les mécanismes moléculaires mis en place lors de la Chimiothérapie Hyperthermique Intra péritonéale (CHIP) pouvant expliquer les effets bénéfiques observés chez les patients atteints d’une carcinose péritonéale (CP). Une partie de ces bénéfices sont dus à la mise en place d’une immunité anti-tumorale. En utilisant des modèles in vivo et in vitro j’ai mis en évidence l’implication de la protéine du choc thermique 90 (Hsp90) dans l’effet observé. Ainsi, l’inhibition spécifique de la Hsp90 réverse les effets protecteurs de la CHIP, soulignant l’importance de cette protéine dans notre modèle d’immunité anti-tumoraleThe link between cell metabolism and cancer at the cellular level has long been known. Caloric restriction (CR) is known to prolong lifespan and to protect from cancer incidence. The molecular mechanisms involved in these benefic effects have been evaluated and may offer new opportunities for therapeutic intervention. Moreover, CR and CR-mimetics such as 2-deoxyglucose (2DG) has been shown to enhance chemotherapy efficiency and to induce an anti-cancer immune response. During the period of my PhD I demonstrated how the modulation of metabolism through caloric restriction or through its mimetics could significantly reduce the expression of the anti-apoptotic protein Mcl-1 and sensitize lymphoma-bearing mice to apoptosis induced by a Bcl-2/XL inhibitor, ABT-737. We have demonstrated that CR can control Mcl-1 translation and sensitize cells to ABT-737-induced death regardless of the presence or absence of p53 and/or of the main “BH3-only proteins”. Then, I focused on deciphering the molecular mechanisms allowing the Hyper-thermic Intra-Peritoneal Chemotherapy (HIPEC) to be beneficial to patients suffering from peritoneal carcinomatosis. Part of the protective effect was mediated through the induction of an efficient anti-cancer immune response. Next, I showed the involvement of heat shock proteins 90 (Hsp90) in the observed effect. Indeed, when Hsp90 was blocked we lost the protection induced by the HIPEC-treated cells, therefore underling the role of Hsp90 in this HIPEC-dependent induction of anti-cancer immune response
4
Decque, Adrien. „Etude de la SUMOylation dans l’immunité innée et l’oncogenèse“. Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066312/document.
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La SUMOylation est une modification post-traductionnelle réversible permettant de diversifier les fonctions de centaines de substrats. Elle est impliquée dans des processus essentiels à la cellule et à l'organisme, tels que la réparation de l'ADN, la mitose, la transcription. A l'aide de modèles murins génétiquement modifiés déficients pour l'unique enzyme E2 de SUMOylation, UBC9, nous avons caractérisé les conséquences de la réduction de la SUMOylation sur l'immunité innée et l'oncogenèse.Nous révélons un rôle majeur de la SUMOylation dans la régulation négative du gène codant pour l'IFN- . La dérégulation de ce gène par l'absence d'Ubc9 a des conséquences importantes sur l'immunité innée, avec une augmentation de l'expression du programme transcriptionnel inflammatoire, une hypersensibilité au choc endotoxique, et une protection contre les infections virales. L'étude du profil chromatinien de SUMO autour du gène Ifnb1 a révélé trois nouveaux domaines à potentiel régulateur. Enfin, la SUMOylation régule l'expression de rétrovirus endogènes, potentiellement déclencheurs d'une réponse interféron.Le second axe de recherche a permis de caractériser les conséquences de la réduction de la SUMOylation sur la transformation cellulaire et l'oncogenèse colorectale. Nous montrons une sensibilité accrue des cellules transformées à la perte de SUMOylation comparées aux cellules primaires. De plus, les souris hétérozygotes pour Ubc9 présentent une réduction du nombre de polypes intestinaux dans un modèle d'oncogenèse colorectale.Ces résultats permettent d'affiner nos connaissances sur le rôle de la SUMOylation dans l'oncogenèse et l'immunité innéeSUMOylation is a reversible post-translational modification modifying the functions of hundreds ofproteins. It is implicated in essential cellular and organismal processes, such as nuclear shuttling, DNArepair, mitosis, transcription. Using genetically modified models, deficient for the uniqueSUMOylation E2 enzyme UBC9, we characterized the consequences of a decrease in globalSUMOylation in two processes: innate immunity and oncogenesis.We reveal a major role for SUMOylation in the negative regulation of the gene coding for IFN-.Deregulation of this gene in the absence of Ubc9 has dramatic consequences on innate immunity, withincreased inflammatory transcriptional program expression, endotoxic shock hypersensitivity, andprotection against viral infection. Chromatin binding profile analysis of SUMO surrounding the Ifnb1gene revealed three new putative regulatory domains. Finally, SUMOylation regulates endogenousretroviruses expression, potential triggers for interferon response.Our second research axis allowed the characterization of the consequences of global SUMOylationdecrease on cellular transformation and colorectal oncogenesis. Our results show increased sensitivityof transformed cells to SUMOylation loss, when compared to primary cells. Furthermore, decreasingUBC9 levels by half causes a two-fold decrease in intestinal polyp numbers developing in the colon ofmice, in a chemically-induced model of colorectal oncogenesis.Altogether, these results helped increasing our knowledge of the role of SUMOylation in majorcellular processes implicated in oncogenesis and innate immunity
5
Meyer, Andrea Michael. „Ro52 in innate immunity, proliferation control and cancer /“. Zürich : ETH, 2009. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=18198.
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6
Al, Khathami Ali Gaithan. „Towards gastric cancer immunotherapy : assessment of cancer immunity and potential immune targets“. Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8855/.
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Gastric cancer (GC), the fourth most common malignancy worldwide, has poor prognosis and treatment innovation is needed. The aims of this project were to investigate immune targets and treatment strategies for GC. I identified new T-cell epitopes in three Epstein-Barr virus (EBV) tumor antigens, LMP1, LMP2 and BARF1, expressed in the 10% of GC cases positive for EBV. T-cell clones showed that a BARF1-specific CD4 T-cell epitope restricted by HLA-DR51, an allele common in the population, was presented by an EBV-positive epithelial cancer cell line. Analysing blood and fresh tumor from newly diagnosed GC patients, I detected T-cell responses to MAGEA1, MAGEA4 and NY-ESO-1 tumour antigens in blood but not tumor. Compared to healthy donors, patients had: higher frequencies of LAG3 or CTLA4 positive CD8 T-cells, TIM-3 or CTLA4 CD4+ T-cells, T-regs, NKT-cells and gamma-delta T-cells in blood and tissue. Patients also had high granulocytic MDSC frequencies in PBMC. The CD4:CD8 ratio was low in some patients' blood, potentially indicating immunosenesence, but was always higher in tumor tissue. I successfully generated tumour infiltrating lymphocytes (TILs) from nine patients' tumors. These comprised high T-cells and NK-cells and low T-reg and MDSC. LAG-3 was increased, but PD1, was decreased on TIL T-cells. Using 3-dimensional organoids established from two patients, I showed that TIL NK-cells, but not TIL T-cells, recognized autologous tumor organoids. My results are the first proof of principle that TILs can readily be generated from gastric tumors, can target tumors cells and therefore be used to treat gastric cancer.
7
Titu, Liviu. „Specific cytotoxic lymphocyte immunity against telomerase in colorectal cancer“. Thesis, University of Hull, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273656.
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8
Gajurel, Damodar. „Boosting Anti-Cancer Immunity with a Novel Chimeric Molecule“. Thesis, Griffith University, 2017. http://hdl.handle.net/10072/370742.
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High mortality, second only to cardiovascular causes, and high morbidity (physical as well as psychological) from cancer are unacceptable. Despite many years of multi-modality (conventional) treatment with surgery, radiotherapy, and chemotherapy, the status of cancer management, especially lung cancer, is still not satisfactory and alternate management strategies need to be developed.
Anti-tumour immunotherapy is being explored as a potential new form of cancer therapies. Cancer vaccines, as forms of immunotherapy, have been developed and tested in clinical trials. Unfortunately, almost all of them did not achieve expected clinical responses. One of the reasons for this failure has been attributed to the poor immunogenicity/antigenicity of those vaccines. It has been suggested that whole tumour cells, harbouring all known and unknown cancer antigens, would better serve as vaccine antigens by circumventing the probability of tumour antigen loss due to tumour immune editing than selected single antigens used in most of those failed trials. The fact that even histologically similar types of tumours can harbour divergent antigens in different patients also explains the failure of clinical trials using allogeneic cancer cell vaccines suggesting that personalized tumour vaccines using autologous whole tumour cells would most likely ensure clinical success of cancer vaccines. But, at the same time, studies have shown that, in contrast to isolated single antigens, whole cancer cells also contain self-antigens that could lead, if not to outright immune tolerance, then to poor immune response, necessitating the use of immune-potentiating adjuvants to garner sufficient anti-tumour immune stimulation, i.e. enhanced immunogenicity. Therefore, combining autologous whole cancer cells with the appropriate immune-potentiating adjuvant in various novel ways could ensure a highly immunogenic and clinically effective vaccine.
Considering the above facts, this study has been initiated to design a lung cancer vaccine with improved immunogenicity by conjugating a known strong and safe immune-potentiating adjuvant, i.e. unmethylated cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN) to whole A549 human lung cancer cell (as vaccine antigens) with the help of cross-linker bis-sulfosuccinimidyl suberate (BS3) in a novel way. Studies have shown that bi-directionally active NHS-ester moiety of BS3 covalently attach to the surface of the cancer cell membrane on one side and to one end of CpG ODN on the other side forming a novel chimeric molecule with 100-fold enhanced immune-potentiating capacity compared to their use in physical and temporal isolation. The formation of this covalently stable chimeric molecule using A549 whole lung cancer cells with CpG ODN, for the first time, was confirmed using fluorescein molecule tagged CpG ODNs and a scanning laser confocal microscope.
The immunogenicity of this novel chimeric molecule was tested in vitro by measuring the level of the cytokines interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α) released after exposure to U937 differentiated macrophages.
The results of the level of the cytokines confirm that quantitatively more IL-6 and TNF-α, as surrogate markers for anti-cancer immune response, were released with the incorporation of the novel chimeric molecule than its control. The chimeric molecule induced the release of about 4500 pg/ml of TNF-α. This was very close to the amount of TNF-α (about 5000 pg/ml) released by 100 ng/ml of lipopolysaccharide (LPS) used as positive control. The negative control i.e. unconjugated CpG ODN and macrophages, released only around 500-600 pg/ml of TNF-α (i.e. our novel chimeric molecule induced nine times more cytokine release than its control. The difference in means of the cytokines released by them was also statistically significant (p < 0.05).
The results indicated that this novel chimeric molecule is highly immunogenic and could be further tested in animal models as the next step towards the development of a personalized anti-lung clinical cancer vaccine.Thesis (Masters)
Master of Medical Research (MMedRes)
School of Medical Science
Griffith Health
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9
Lemay, Chantal. „Harnessing Oncolytic Virus-mediated Anti-tumour Immunity“. Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/23318.
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Treatment of permissive tumours with the oncolytic virus (OV) VSV-Δ51 leads to a robust anti-tumour T cell response, which contributes to efficacy; however, many tumours are not permissive to in vivo treatment with VSV-Δ51. In an attempt to channel the immune stimulatory properties of VSV-Δ51 and broaden the scope of tumours that can be treated by an OV, a potent oncolytic vaccine platform was developed, consisting of tumour cells infected with VSV-Δ51. I demonstrate that prophylactic immunization with this infected cell vaccine (ICV) protected mice from subsequent tumour challenge, and expression of GM-CSF by the virus (VSVgm-ICV) increased efficacy. Immunization with VSVgm-ICV in the VSV-resistant B16-F10 model induced maturation of dendritic cells, natural killer (NK) cells, and T cells. I demonstrate that this approach is robust enough to control the growth of established and spontaneous tumours. This strategy is broadly applicable because of VSV’s extremely broad tropism, allowing nearly all cell types to be infected at high MOIs in vitro, where the virus replication kinetics outpace the cellular IFN response. It is also personalized to the unique tumour antigen(s) displayed by the cancer cell. Histone deacetylase inhibitors (HDIs) can augment viral replication, making them particularly interesting complements to OV therapy. However, the impact of HDIs on the generation and re-stimulation of immune responses remains to be clearly elucidated. Along with my collaborators at McMaster University, I demonstrate that MS-275, but not SAHA, selectively depletes naïve and regulatory lymphocytes. Memory lymphocytes that are being boosted remain unscathed and even have enhanced cytokine production, potentially as a consequence of the depleted lymphocyte compartment. This leads to a delay in anti-VSV neutralizing antibodies and T cell responses. Interestingly, HDI treatment of B16-F10 cells appears to inhibit VSV replication but allows for a longer persistence within the tumour. When used in an oncolytic prime/boost vaccination model, MS-275 potently enhanced survival. Though the anti-tumour immune response is enhanced, a near complete reduction in autoimmune vitiligo is observed with MS-275 administration. Therefore, this HDI uniquely modulates the immune response to enhance anti-tumour immunity and decrease the anti-viral response, while also decreasing autoimmune sequelae.
10
Aloulou, Nijez. „Rôle de la leptine dans le cancer colorectal humain“. Thesis, Paris Est, 2008. http://www.theses.fr/2008PEST0027.
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Par sa fréquence et sa gravité, le CCR représente un réel problème de santé publique. Avec 37000 nouveaux cas par an et 15% des décès, il constitue la 2ème cause de mortalité par cancer en France. Malgré d'importants progrès thérapeutiques durant cette dernière décennie, il rest un cancer de mauvais pronostic. Des facteurs génétiques et environnementaux ont été impliqués dans la genèse de ce cancer. La caractérisation moléculaire du CCR a permis d'identifier les tumeurs par instabiblité génique, appelées MSI (Microsatelite Instability) possédant des anomalies de réparation d'appariement d'ADN (MMR mismatch repair). Celles-ci sont fréquemment retrouvées (80%) dans les CCRs familiaux et rarement (15%) dans les cancers sporadiques. Les tumeurs avec phénotype MSI sont de bon pronostic. Le rôle possible de l'alimentation et particulièrement celui du fuel énergétique sur la survenue d'anomalies d'appariement d'ADN a été suggéré. De nombreuses hormones et en particulier la leptine ont été rapportées comme facteur de promotion tumorale. De plus, la leptine possède de nombreuses propriétés immunrégulatrices. Son effet sur l'immunité colique tiendrait autant à sa capacité à initier la production de cytokines à partir des cellules épithéliales digestives qu'à sa capacité à contrôler la prolifération des lymphocytes. Nous avons formulé l'hypothèse que la leptine pouvait réguler des fonctions immunes dans le microenvironnement tumoral. L'ensemble de ces données souligne l'importance de l'étude chez l'homme. L'analyse des données prospectives de 171 patients avec CCR permet de noter une surexpression du récepteur de la leptine dans un sous groupe de tumeurs. Les relations entre le récpteur de la leptine et la réponse immunitaire ont été analysées dans le microenvironnement tumoral humain, par des modèles cellulaires in vitro et animaux in vivo. Nous avons découvert que l'effet pro immunitaire de leptine dépendait du niveau d'expression de sonrécepteur et du degré d'instabilité microsatellitaire dans la cellule tumorale. L'expression du récepteur de la leptine pourrait être considérée comme un marqueur pronostique dans le CCR humainCancer of the colon and rectum (CRC) is a real challenge in Western countries because of the prevalence, cost and bad prognosis. With they 37,000 new cases each year and 15% of mortality it is currently the 2nd cause of cancer death in France. Despite significant advances in diagnosis and treatment over the past decade, it remains with bad prognosis. Genetic and environmental factors were involved in the genesis of this cancer. Molecular characterization of CRC leaded to the identification of gene instability (MSI) in tumors with mismatch repair (MMR) abnormalities. This is found frequently (80%) the CRC hereditary no polyposis colon cancer family (HNPCC) and rarely (15%) in sporadic cancers. Those tumors with MSI phenotype are considered to be of good prognosis. The possible role of food and particulary energy balance on the occurrence of MMR abnormalities has been suggested. Several hormones including leptin have been reported to promote tumour growth. In addition, leptin may regulate immune response tin GIT. Its pro immunogenic effect results from cytokines production by gastrointestinal epithelial cells as well as its ability to control the proliferation of lymphocytes. We hypothesised that leptin might regulate anti tumour immune response. The analysis of prospective data from 171 patients with CRC showed that overexpression of leptin receptor in subset of tumours. Relationships between leptin recptor and tumour immune response have been studied in the tumour microenvironment in human tissues, and in culture cells in vitro as well as in animal models in vivo. Results showed intensity of immune response was depended on the level of leptin receptor expression and MSI in colon tumour cells. Thus leptin receptor expression may be considered as a prognostic marker in colon and rectal cancer in human
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Thornton, Lisa Marie. „Stress and immunity in a longitudinal study of breast cancer patients“. Connect to resource, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1117578022.
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12
Hollingworth, James. „The manipulation of cellular immunity by monoclonal antibodies in cancer patients“. Thesis, University of Leicester, 1994. http://hdl.handle.net/2381/34109.
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The role of an immune response in the development and regulation of tumour growth is outlined. The historical development of immunotherapy in the treatment of human cancer is reviewed and the mechanisms by which immunity may be manipulated in vitro and in vivo with respect to improving cancer immunotherapy are discussed. The experimental studies and laboratory methods finally used are presented and validated in chapter 3. Non-major histocompatibility-restricted cellular cytotoxicity was assessed in a standard 4-hour 51chromium-release assay and peripheral blood cell populations were examined using fluoresceine-conjugated monoclonal antibodies and flow cytometry. Initially in vitro studies of cellular cytotoxicity against cultured tumour cells were undertaken using peripheral blood mononuclear cells (PBMC) obtained from healthy volunteers. Extremely variable levels of cellular cytotoxicity were documented in these healthy donors which were unrelated to age or sex but were positively correlated with numbers of circulating natural killer (NK) cells. The effect on cytotoxicity, of preincubating PBMC with monoclonal antibodies (mAb) and interleukin 2 (IL-2) was studied. Various mAb including those to the CD3 antigen were found to enhance cellular cytotoxicity in vitro. The mechanism of enhancement remained unproven. However, preliminary studies suggested that mAb redirected effector cells by interacting with Fc receptors on the surface of tumour cells. Combinations of mAb had a partially additive effect on enhancement of cytotoxicity. IL-2 also enhanced cytotoxicity in a dose dependent manner although synergy between IL-2 and anti-CD3 was not demonstrated. PBMC were then studied from patients with advanced gastrointestinal tract cancer. Levels of cellular cytotoxicity were not significantly related to tumour extent and were similar to cytotoxicity in healthy donors. Cytotoxicity was mediated mainly by NK cells although lymphocytes coexpressing the CD3 antigen and NK surface antigens were significantly increased in cancer patients compared with healthy donors and also in patients with liver metastases compared to those without liver involvement. In cancer patients with liver metastases, lymphocytes coexpressing the CD3 antigen and NK antigens may play a more significant role in K562 cytotoxicity. Cytotoxicity was also enhanced in vitro by anti-CD3 mAb and I1-2. A clinical study was undertaken to investigate the safety and the immunomodulating properties of administering between 50 mug and 0.5 mug of OKT3 or normal saline to patients with advanced cancer. Patients experienced minimal and self- limiting dose-related side effects. Only one patient developed evidence of cytokine release following OKT3 when assessed by enzyme-linked immunosorbent assays. Depletion of circulating T cells and NK cells occurred following OKT3 which was proportional to the dose administered. Lymphocyte activation assessed by interleukin 2 receptor expression was not detected. Considerable individual variation in cytotoxicity was related to variation in NK cell numbers in blood in both OKT3 and normal saline treated patients. 50 mug OKT3 was associated with a rapid decline in both circulating NK cells and cytotoxicity at 4 hours compared with lower doses of OKT3. The lower doses of OKT3 had a variable effect on cytotoxicity at 24 hours. 20 mug and 5 mug OKT3 was associated with a significant rise in cellular cytotoxicity at 24 hours compared with untreated controls and the 10 mug dose. These results demonstrate that anti-CD3 mAb enhance cellular cytotoxicity in vitro. The effect of OKT3 on lymphocyte function in vivo is dose-related and variable. Low doses of OKT3 may either enhance or depress cellular immunity depending upon the precise dose and time of study following administration. The relationship between the in vitro effects of anti-CD3 mAb on cellular cytotoxicity and their effects in vivo are uncertain. Although low doses of OKT3 may be safely administered to cancer patients further studies are needed to define its potential in human cancer immunotherapy.
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Maugeri, P. M. „STATES OF CANCER IMMUNITY: THE ETHICAL DIMENSIONS OF HPV VACCINATION POLICIES“. Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/214786.
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Human Papillomavirus (HPV) is a sexually transmitted virus, recognized to be the necessary, yet not sufficient, cause of cervical cancer. Vaccines for individual administration targeting HPV are available today. In this dissertation I undertake a normative analysis of existing HPV vaccination programmes and evaluate how current policy alternatives put in balance competing moral concerns at stake. To this aim, I explore the ethical dimension of the different policy models, with respect to issues of respect for individual choice, expected coverage rates, and population health goals.
My goal is thus to show how the different policies - ranging from a hotly contested mandatory model to prima facie more justifiable voluntary approaches – fare with respect to the interests of individuals targeted by HPV vaccination campaigns. Differently from standard approaches in public health ethics, however, I show that concerns for individual choice in HPV contexts cannot be severed by equally important concerns for social justice. In particular, I show that an insistence on the least restrictive alternative alone leaves out of focus important concerns for social justice and the need to avoid the worsening of existing inequalities. Moreover, I argue that standard approaches in public health ethics should be widened to consider the legitimate interests of specific social groups, namely those belonging to socio-economically disadvantaged strata of society, and fair consideration of the health interests of minority groups.
In this dissertation I therefore present a rationale for adopting a capability-based approach to HPV immunization in order to cope with the most pressing ethical issues at stake in this field.
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Seipp, Robyn Patricia. „The role of tapasin and its isoforms in antigen presentation and tumor immunity“. Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/558.
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Major Histocompatibility Complex (MHC) Class I molecules present peptides to CD8⁺ T cells and are essential for most adaptive immune responses. The first described-spliced tapasin (“isoform 1”) plays a critical role in MHC-I antigen presentation by facilitating peptide loading onto MHC-I molecules in the endoplasmic reticulum (ER). This thesis examines the expression, localization and function of two novel, alternatively-spliced isoforms of human tapasin that lack exon 7 (“isoform 2”) or both exons 6 and 7 (“isoform 3”). Isoform 1 contains a di-lysine ER-retention motif; the two novel isoforms encode different carboxy (C) termini that lack this motif. It was hypothesized that isoforms 2 and 3 would function in MHC-I cross-presentation of exogenous antigens in non-ER compartments. Isoform 2, like isoform 1, was found to be mainly ER-localized; however, both these isoforms were also found to co-localize in smaller amounts with the trans Golgi network and endo/lysosomes by confocal microscopy. Isoform 3 lacks a transmembrane domain and was found to be secreted from cells as well as being found within the ER. All isoforms were widely expressed at the RNA level in many tissues and cell types; however, mature dendritic cells (DCs) expressed the highest levels of all three isoforms, consistent with the high cross-presenting abilities of DCs. Both isoform 1 and 2 stabilized the transporters associated with antigen processing (TAP) in murine tapasin-/- cells, but isoform 3 did not due to its missing transmembrane domain. Isoform 1 and 2 mediated very similar effects on endogenous MHC-I presentation of self and viral peptides, on surface MHC-I thermostability, and on MHC-I maturation rates. Isoform 3 was found to decrease loading of exogenous peptides onto MHC-I. None of the isoforms influenced cross-presentation of the soluble antigen ovalbumin in a mouse dendritic cell line.
This thesis also examines the effect of antigen presentation machinery (APM) re-expression in MHC-I-deficient tumor cell lines, B16F10 and CMT.64, which are deficient in TAP and tapasin. Virally-driven TAP1 and Tapasin expression increased MHC-I expression in the tumor cell lines, augmented tumor cell immunogenicity, and decreased tumor growth in vivo due to increased tumor cell elimination by the immune system.
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Darwish, Ammar. „Systemic and mucosal immunity in patients with periampullary cancer, obstructive jaundice and chronic pancreatitis“. Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/systemic-and-mucosal-immunity-in-patients-with-periampullary-cancer-obstructive-jaundice-and-chronic-pancreatitis(b6e3ee83-3e4e-4b34-8c36-8eb75c3961cc).html.
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Introduction: Derangement of systemic and mucosal immunity, which are the integral components of the immune system, increases the risk of septic complications in patients postoperatively. The aims of this study were to investigate the integrity of systemic immunity as well as the mucosal immune system in patients with pancreatic cancer (PC), chronic pancreatitis (CP) and obstructive jaundice (OJ).Method: Healthy controls, as well as four groups of patients were studied. These included; jaundiced patients with PC, jaundiced patients secondary to benign disease (choledocholithiasis), non-jaundiced patients with PC and non-jaundiced patients with CP. The study evaluated the nutritional status including anthropometric measurements and the serum proteins: retinal binding protein (RBP), transferrin (TRF) and prealbumin (PALB). This study also evaluated systemic immunity in terms of total lymphocyte count, lymphocyte subsets (CD4+, CD8+, CD25+and CD56+), tumour necrosis factor alpha (TNF- alpha), interleukin-1alpha (IL-1 alpha) and complement components; and mucosal immunity in terms of CD3+, CD4+, CD8+, CD20+, CD57+, CD68+ and mast cells. Results: 78 patients were recruited (including 39 males) as follows: normal controls (n=17), benign OJ (n=9), patients with PC with jaundice (n=23), non-jaundiced patients with PC (n=20) and CP (n=9). Circulating CD25+ and CD4+ were significantly lower in the PC group whereas CD8+ showed increased levels in the same patients with a significant decrease in OJ patients when compared with controls. Circulating CD56+ showed no statistically significant difference between all four groups. In addition, IL-1 and TNF-alpha showed no statistically significant difference in all groups when compared with the control group. Also, C3 and CH50 showed significantly raised levels in PC with jaundice when compared with the control group. On the other hand mucosal lymphocyte subsets showed no statistically significant difference among all groups in comparison with the control group. As for prealbumin and transferrin, both showed significantly low levels in OJ, PC with jaundice and with PC when compared to healthy controls. Survival analysis for both PC groups was carried out and showed no difference in terms of age, however PC patients who survived over 13 months showed increased levels of prealbumin as well as low levels of CH50.Conclusion: Patients with PC both with and without jaundice showed some signs of altered and dysfunctional systemic immunity as well as a reduction in serum proteins. These findings may have implications on the disease progression and postoperative complications. This may warrant therapeutic interventions to restore nutrition and improve immunity before major surgical intervention is planned which could result in improving prognosis.
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Decque, Adrien. „Etude de la SUMOylation dans l’immunité innée et l’oncogenèse“. Electronic Thesis or Diss., Paris 6, 2014. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2014PA066312.pdf.
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La SUMOylation est une modification post-traductionnelle réversible permettant de diversifier les fonctions de centaines de substrats. Elle est impliquée dans des processus essentiels à la cellule et à l'organisme, tels que la réparation de l'ADN, la mitose, la transcription. A l'aide de modèles murins génétiquement modifiés déficients pour l'unique enzyme E2 de SUMOylation, UBC9, nous avons caractérisé les conséquences de la réduction de la SUMOylation sur l'immunité innée et l'oncogenèse.Nous révélons un rôle majeur de la SUMOylation dans la régulation négative du gène codant pour l'IFN- . La dérégulation de ce gène par l'absence d'Ubc9 a des conséquences importantes sur l'immunité innée, avec une augmentation de l'expression du programme transcriptionnel inflammatoire, une hypersensibilité au choc endotoxique, et une protection contre les infections virales. L'étude du profil chromatinien de SUMO autour du gène Ifnb1 a révélé trois nouveaux domaines à potentiel régulateur. Enfin, la SUMOylation régule l'expression de rétrovirus endogènes, potentiellement déclencheurs d'une réponse interféron.Le second axe de recherche a permis de caractériser les conséquences de la réduction de la SUMOylation sur la transformation cellulaire et l'oncogenèse colorectale. Nous montrons une sensibilité accrue des cellules transformées à la perte de SUMOylation comparées aux cellules primaires. De plus, les souris hétérozygotes pour Ubc9 présentent une réduction du nombre de polypes intestinaux dans un modèle d'oncogenèse colorectale.Ces résultats permettent d'affiner nos connaissances sur le rôle de la SUMOylation dans l'oncogenèse et l'immunité innéeSUMOylation is a reversible post-translational modification modifying the functions of hundreds ofproteins. It is implicated in essential cellular and organismal processes, such as nuclear shuttling, DNArepair, mitosis, transcription. Using genetically modified models, deficient for the uniqueSUMOylation E2 enzyme UBC9, we characterized the consequences of a decrease in globalSUMOylation in two processes: innate immunity and oncogenesis.We reveal a major role for SUMOylation in the negative regulation of the gene coding for IFN-.Deregulation of this gene in the absence of Ubc9 has dramatic consequences on innate immunity, withincreased inflammatory transcriptional program expression, endotoxic shock hypersensitivity, andprotection against viral infection. Chromatin binding profile analysis of SUMO surrounding the Ifnb1gene revealed three new putative regulatory domains. Finally, SUMOylation regulates endogenousretroviruses expression, potential triggers for interferon response.Our second research axis allowed the characterization of the consequences of global SUMOylationdecrease on cellular transformation and colorectal oncogenesis. Our results show increased sensitivityof transformed cells to SUMOylation loss, when compared to primary cells. Furthermore, decreasingUBC9 levels by half causes a two-fold decrease in intestinal polyp numbers developing in the colon ofmice, in a chemically-induced model of colorectal oncogenesis.Altogether, these results helped increasing our knowledge of the role of SUMOylation in majorcellular processes implicated in oncogenesis and innate immunity
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Calvet, Christophe. „Immunological aspects of anticancer electroporation-based treatments“. Thesis, Paris 11, 2014. http://www.theses.fr/2014PA114816.
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L'électrochimiothérapie est un traitement anticancéreux utilisé en routine en Europe dans près de 130 centres de traitement du cancer. Le taux de réponse objective atteint 85 % pour le traitment de tumeurs cutanées et sous-cutanées et des études sont en cours afin d'appliquer ce traitement à des tumeurs profondes. Au cours de ce doctorat, les méchanismes sous-jacents à cette excellente efficacité antitumorale ont été étudiés. Dans un premier temps, l'objectif a été d'évaluer la capacité de l'électrochimiothérapie à induire la mort des cellules souches cancéreuses, considérées comme les racines du cancer. Ensuite, les mécanismes immunologiques à l'origine du développement d'une immunité antitumorale mise en place par le traitement ont été investigués. Cependant, malgré le haut taux de réponse observé, l'électrochimiothérapie reste un traitement local qui n'induit pas de réponse antitumorale à distance, sur les tumeurs non-traitées. Afin de pallier à cette absence d'activité systémique, une collaboration a été mise en place avec une entreprise innovante de biotechnologies, INVECTYS, dans le but de développer une stratégie de vaccination à ADN ciblant la télomérase et basée sur l'électrogènetransfert. Il est attendu que la combinaison de cette immunothérapie avec un traitement local par électrochimiothérapie, détruise non seulement la tumeur primaire, dont les cellules souches cancéreuses, mais également les cellules cancéreuses circulantes et les métastasesElectrochemotherapy is an anticancer treatment used in routine in Europe in 130 cancer treatment centers. The objective response rate reaches 85 % for the treatment of cutaneous and subcutaneous tumors and studies are ongoing to spread the use of electrochemotherapy to deep-seated tumors. In the frame of this doctorate, the mechanisms underlying this excellent antitumor efficiency were investigated. First, the goal was to evaluate the ability of electrochemotherapy to induce the death of cancer stem cells, considered as the roots of cancer. Second, the immunological mechanisms responsible for the development of antitumor immune responses following the treatment were investigated. However, although a very high response rate is observed, electrochemotherapy remains a local treatment which does not induce antitumor responses in distant non-treated nodules. In order to circumvent this lack of systemic activity, a collaborative project was initiated with an innovating biotech company, INVECTYS, in order to develop a DNA vaccination strategy targeting the telomerase and based on electrogenetransfer. It is expected that the combination of this immunotherapy with a local treatment by electrochemotherapy could destroy not only the primary tumor, including cancer stem cells, but also circulating cancer cells and metastases
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Allen, Paul David. „Investigation into the effects of suramin and interleukin-2 on anti-tumour immunity“. Thesis, Queen Mary, University of London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309057.
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The use of rhIL-2 to augment antitumour immunity was seen as having great potential for the treatment of neoplasia, but the efficacy of immunotherapy has remained poor despite encouraging experimental data. A reason for this could be active immunosuppression by the tumour mediated by the secretion of suppressor factors. Suramin is a polyanionic drug which blocks and inhibits a range of growth factors and cytokines. This project investigates the potential of suramin to act as an adjunct to rhIL-2 based immunotherapy by acting as a blockade to suppressor factors. In vitro studies showed that rhIL-2 generation of LAK cells resulted in an increase in expression of activation associated antigens, a proliferation of cytotoxic T cells and natural killer cells and augmentation of cytolytic activity. These parameters could be suppressed by factors released from the colorectal cell line LoVo, but co-culture with suramin reversed the suppression in cells isolated from normal individuals. A suramin induced fall in the percentage of cells expressing CD4 was shown to be due to CD4 modulation and not the apoptotic death of CD4+ve cells. CD4 modulation could be reversed by the removal of suramin and could be influenced by tyrosine kinase inhibitors, though direct tyrosine phosphorylation of CD4 did not occur. The CBHlCBi Hooded rat was used as an in vivo model to study the potential of suramin and rhIL-2 in controlling induced liver metastasis from the syngeneic HSN sarcoma cell line. A toxicology study showed suramin side effects to include a reduction in total body weight gain and an increase in lymph node and spleen weights. Enlargement of kidneys and reduction in liver size were also seen. Haematologically, a suramin induced basophilia and thrombocytopenia were recorded as well as a rhIL-2 induced eosinophilia. In vivo CD4 modulation was also seen. Finally a combined suramin and rhIL-2 therapy regimen was found to be more effective than either agent alone in reducing both hepatic tumour mass and numbers after the induction of metastases in these animals. It was concluded that suramin can be used as an adjunct to rhIL-2 based immunotherapy.
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Marcheteau, Elie. „Effet de l'inhibition par ARN interférence de la thrombospondine-1 sur la potentialisation de la réponse immune dans un contexte tumoral“. Thesis, Toulouse 3, 2019. http://www.theses.fr/2019TOU30083.
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Le cancer du sein est actuellement le cancer le plus fréquent et le plus mortel chez la femme. Malgré le fait que la prise en charge des patientes ait été améliorée dans nos sociétés occidentales au cours des dernières années, la principale cause de mortalité reste la dissémination métastatique. Force est de constater que de nombreuses stratégies thérapeutiques, comme des traitements anti-angiogéniques ou des immunothérapies ciblant des points de contrôle immunitaire, sont toujours en échec dans ce type de cancer, notamment dans les cancers du sein triple négatifs (TNBC), forme la plus agressive. L'hypoxie tumorale est un facteur de mauvais pronostic car facilitant la dissémination métastatique et inhibant la réponse immunitaire anti-tumorale. Dans ce contexte, la Thrombospondine-1 (TSP1), un anti-angiogène endogène majeur, a été décrite comme activatrice de TGFß, une cytokine immunosuppressive facilitant la transition épithélio-mésenchymateuse des cellules cancéreuses. Nous avons émis l'hypothèse que cibler la TSP1 dans les TNBC permettrait non seulement de normaliser l'angiogenèse tumorale mais aussi de faciliter la réponse immunitaire. Des analyses de bases de données publiques nous ont permis de montrer qu'une forte expression de TSP1 dans les biopsies tumorales est associée à une signature génique d'immunoéchappement et à un mauvais pronostic chez les patientes atteintes de TNBC. En accord avec ces observations, nos analyses d'immunohistochimie montrent une corrélation inverse entre l'infiltrat tumoral des lymphocytes T CD8+ et l'expression de TSP1 dans des biopsies tumorales de TNBC. Dans un modèle préclinique de TNBC, basé sur l'injection orthotopique de cellules 4T1, l'inhibition de la TSP1 par interférence ARN dans les cellules tumorales (i) augmente significativement le nombre de vaisseaux au sein des tumeurs et l'infiltration intratumorale des lymphocytes, incluant les lymphocytes T CD8, (ii) diminue la dissémination métastatique des 4T1 chez les souris immunocompétentes, mais pas chez les souris Nude, (iii) augmente la réponse aux anti-PD-1. En conclusion, nos résultats montrent que la TSP1, produite par les cellules cancéreuses de TNBC, favorise un remodelage vasculaire, inhibe l'infiltration lymphocytaire et facilite la dissémination métastatique. Cibler la TSP-1 permet de réorganiser le microenvironnement tumoral, augmentant la réponse immunitaire anti-tumorale et la réponse aux anti-PD-1. Ainsi, cette étude ouvre vers de nouvelles perspectives thérapeutiques chez les patientes atteintes de TNBC et vise à combiner des thérapies "anti-anti-angiogéniques" et des immunothérapies comme les anti-PD-1Breast cancer is currently the most common and fatal cancer in women. The main cause of death remains metastatic dissemination despite the improvement of patient care in Western societies during the last few years. It is clear that recent therapeutic strategies, such as anti-angiogenic treatments or immunotherapies targeting immune checkpoints, are still failing to eliminate this type of cancer, especially in triple negative breast cancer (TNBC), the most aggressive form of breast cancer. At least part of the inhibition of anti-tumor immune response could be due to tumor hypoxia, a poor prognostic factor also promoting metastatic dissemination. In this context, Thrombospondin-1 (TSP1), a major endogenous antiangiogenic factor, has been described as the main activator of TGFß, an immunosuppressive cytokine facilitating the epithelial-to-mesenchymal transition of cancer cells. We hypothesized that targeting TSP1 in TNBC would not only normalize tumor angiogenesis but also facilitate the immune response. Public database analyses have shown that high TSP1 expression in tumor biopsies is associated with an immune escape gene signature and a poor prognosis in TNBC patients. Consistent with these observations, our immunohistochemistry analyses show an inverse correlation between tumor infiltration of CD8+ T cells and TSP1 expression in tumor biopsies of TNBC. In a preclinical model of TNBC, based on the orthotopic injection of 4T1 cells, the inhibition of TSP1 synthesis by RNA interference in tumor cells leads to (i) a significant increase in the number of vessels within tumors and the tumor infiltration of lymphocytes, including CD8 T cells, (ii) a decrease of metastatic dissemination of 4T1 in immunocompetent mice, but not in Nude mice, (iii) a potentiation of response to anti-PD-1. Collectively, our results show that TSP1 produced by TNBC cancer cells promotes vascular remodelling, inhibition of lymphocyte infiltration and facilitation of metastatic dissemination. Targeting TSP-1 remodelates the tumor microenvironment, increasing the anti-tumor immune response and response to anti-PD-1. Thus, this study opens up new therapeutic strategies in patients with TNBC based on combining "anti-anti-angiogenic" strategies and immunotherapies such as anti-PD-1 treatment
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Draganov, Dobrin Draganov. „MFG-E8 Blockade Enhances Tumor Immunity in a Murine Breast Cancer Model“. Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10512.
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Milk fat globule - epidermal growth factor - factor 8 protein (MFG-E8) is an important mediator of the tolerogenic functions of GM-CSF, and a dominant-negative RGE mutant augments the therapeutic potential of irradiated, GM-CSF-secreting tumor vaccines (GVAX) in the MFG-E8-negative B16 melanoma model. The frequent expression of MFG-E8 in various solid and hematological malignancies, however, prompted us to investigate the effect of the RGE mutant in a MFG-E8-positive transplantable breast tumor model. Here, we report that MFG-E8 blockade augmented anti-tumor humoral responses and modulated immune infiltrates at vaccination sites, which was associated with defective phagocytosis and clearance of apoptotic tumor cells. The RGE mutant enhanced the therapeutic potential of two irradiated, GM-CSF-secreting vaccines and improved protection correlated with augmented tumor-specific IgG1 and IgG2a antibody responses as well as increased ratios of T effectors to Tregs in TILs. These findings are consistent with the notion that MFG-E8 blockade potentiates anti-tumor responses through the preferential expansion of effector over regulatory T cells. Our data also validate the use of the RGE mutant to achieve therapeutically effective MFG-E8 blockade even in the context of tumors and vaccines that express high levels of endogenous MFG-E8.
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Sarvaria, Anushruti. „The differential role of regulatory B cells in cancer and allo-immunity“. Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/55298.
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A new wave of research recognizes a distinct subset of B regulatory cells (Breg) that maintain immune tolerance. Breg cells have been shown to exert immunoregulatory functions through the production of interleukin (IL)-10 and appear to play important roles in autoimmunity and in cancer. Despite the extensive body of evidence reinforcing the notion of B cells as potential regulatory cells, some controversy over the paucity of markers that can unequivocally identify Bregs still exists. To study the role of Breg in immune surveillance, I designed a comprehensive multi‐parameter panel of surface antibodies to define B-cell subsets in peripheral blood (PB) and cord blood (CB). The intracellular detection of IL-10 combined with flow cytometric phenotyping presented in my thesis demonstrate the presence of IL-10– producing Bregs with Treg-independent immunosuppressive functions in both the IgM memory (CD19+IgM+CD27+) and transitional (CD19+CD24hiCD38hi) PB B-cell subsets in healthy donors. The regulatory function PB Bregs against CD4+T cells and CD56+NK cells required both cell-cell contact and IL-10 production. Moreover, I demonstrate that Breg populations are expanded in the PB of AML patients and exert potent suppression of NK function mediated through 2B4-CD48 signaling. I further demonstrated the presence of IL-10- producing B cells with Treg-independent immunosuppressive properties in CB with the ability to suppress allogeneic-CD4+T cells through IL-10, as well as cell-cell contact mediated mechanisms involving CTLA-4 and CD80/CD86. I found an early and robust recovery of IL-10+B cells post-CBT. High Breg frequencies in CB may attenuate T-cell responses and contribute to the lower rates of cGVHD. My findings have important clinical implications and suggest that Bregs may be exploited to treat immune-mediated diseases. Whereas, strategies to deplete Bregs for optimal anti-cancer immunotherapy may benefit antitumor activity in AML and other cancers, adoptive transfer of donor-derived Bregs post transplant may offer a potentially effective immunomodulatory therapy for the treatment of GVHD.
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Prat, Mélissa. „Les macrophages au sein du microenvironnement tumoral : étude et modulation des mécanismes moléculaires et cellulaires de la réponse anti-tumorale au cours de carcinoses péritonéales“. Thesis, Toulouse 3, 2019. http://www.theses.fr/2019TOU30116.
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Les macrophages (Mφs) possèdent une remarquable plasticité phénotypique et fonctionnelle qui leur permet de s’adapter aux différents signaux de leur microenvironnement. Au sein du microenvironnement tumoral, les Mφs ou TAMs (Tumor-associated Mφs) représentent la population leucocytaire majeure. Au cours du développement tumoral, les cellules transformées contribuent à éduquer les TAMs qui acquièrent alors des propriétés permissives à la croissance tumorale. Ainsi, il est aujourd’hui admis que les TAMs, initialement de phénotype M1 anti-tumoral, vont se différencier vers un phénotype M2 capable de favoriser la prolifération des cellules tumorales, l’angiogenèse, les métastases, la résistance aux traitements de chimiothérapie et la suppression de la réponse immunitaire adaptative anti-tumorale. Cependant, cette dichotomie fonctionnelle M1/M2, bien que facilitant la description du phénotype des TAMs et de leurs fonctions, est une simplification de la biologie des Mφs au sein du tissu cancéreux qui est en réalité plus complexe. Ainsi, dans la première partie de ce travail de thèse, nous avons montré que l’IL-13, une cytokine Th2 bien décrite pour être impliquée dans la polarisation M2 des Mφs, inhibe la croissance tumorale d’un lymphome T et d’un adénocarcinome ovarien via la promotion de l’activité cytotoxique des Mφs. De manière intéressante, nous avons mis en évidence le rôle clé des récepteurs Lectine de type C Mannose (RM) et Dectine-1, fortement exprimés à la surface des Mφs polarisés par l’IL-13, dans la reconnaissance des cellules tumorales. Nous avons identifié l’acide sialique exprimé à la surface des cellules transformées comme un épitope critique à leur reconnaissance par les Mφs polarisés par l’IL-13. De plus, nous avons montré que, suite à cette reconnaissance, RM et Dectine-1 sont impliqués dans le déclenchement de voies de signalisations cytotoxiques menant à la production de radicaux libres oxygénés et d’arginase, deux médiateurs responsables de l’élimination des cellules tumorales par nécrose. Dans la seconde partie de ce travail, nous avons étudié l’impact du 15(S)-HETE, un ligand naturel du récepteur nucléaire PPAR-γ impliqué dans la polarisation M2 des Mφs, sur le développement tumoral. Nous avons montré que ce lipide inhibe la croissance tumorale dans un modèle murin d’adénocarcinome ovarien. De façon intéressante, nous avons démontré que cet effet anti-tumoral est dépendant de l’activation de PPAR-γ dans les Mφs. Nous avons mis en évidence que le 15(S)-HETE modifie la balance des populations de Mφs présentes au niveau de la cavité péritonéale, probablement en induisant la différenciation des Small Peritoneal Mφs (SPM) en Large Peritoneal Mφs (LPM). Ces derniers possèdent un phénotype qui contribue à augmenter le ratio lymphocytes T effecteurs/régulateurs au niveau de l’ascite tumorale, et ainsi à contrecarrer l’immunosuppression induite par la tumeur. Enfin, dans la troisième partie de ce travail nous mettons en évidence une forte hausse de la population de monocytes intermédiaires (CD14high CD16high) dans le sang d’une cohorte de 19 patientes atteintes de cancer ovarien séreux de haut grade. De manière intéressante, nous avons démontré qu’il existe une corrélation positive entre la présence de cette population intermédiaire au niveau du sang et la présence d’un microenvironnement immunosuppresseur au niveau de l’ascite de ces patientes (↗ Tregs, ↗ TAMS CD163high CD206high CCR2high CD86low et ↘ NK et CD8+ cytotoxiques). De plus, nous avons mis en évidence une corrélation positive entre l’expansion de ces monocytes intermédiaires et le développement tumoral au sein du péritoine. Ensemble, ces données souligne le rôle des monocytes sanguins comme signature prédictive du statut immun et du développement tumoral au sein du péritoine chez des patientes atteintes de cancer ovarienMacrophages, which are crucial effectors of innate immune response, exhibit a remarkable phenotypic and functional plasticity that allows them to adapt to the different stimuli present in their microenvironment. Within the tumor microenvironment, macrophages or TAMs (Tumor-associated macrophages) represent the major leukocyte population. During tumor development, secreted mediators produced by transformed cells « educate » TAMs which acquire properties favorable to tumor growth. Thus, it is now widely accepted that TAMs, initially of anti-tumor M1 phenotype, differentiate towards an M2 phenotype able to promote tumor cell proliferation, angiogenesis, metastases, resistance to chemotherapy treatments and suppression of the adaptive anti-tumor immune response. However, this functional M1/M2 dichotomy, while facilitating the description TAMs phenotype and their associated functions, is an oversimplification of the macrophage biology within tumor tissues which is actually more complex. Thus, in the first part of this work, we showed that treatment with IL-13, a Th2 cytokine well described to be involved in macrophage M2 polarization, inhibits tumor growth in two murine models of T-cell lymphoma and ovarian adenocarcinoma via the promotion of macrophage cytotoxic activity. Interestingly, we demonstrated the key role of Mannose (RM) and Dectin-1 C-type Lectin receptors, strongly expressed on IL-13-activated macrophages, in tumor cell recognition. We specifically identified the sialic acid expressed on transformed cell surface as a critical epitope for their recognition by IL-13-activated macrophages. Moreover, we showed that, following this recognition, RM and Dectin-1 trigger cytotoxic signaling pathways leading to the production of radical oxygen species and the amplification of arginase activity. We finally demonstrated that these two mediators produced by IL-13-activated macrophages induce tumor cell necrosis. In the second part of this work, we studied the impact of 15(S)-HETE, a natural ligand of the PPAR-γ nuclear receptor involved macrophage M2 polarization, on tumor development. We showed that this lipid inhibits tumor growth in an experimental murine model of ovarian adenocarcinoma. Interestingly, we demonstrated that 15(S)-HETE anti-tumor effect depends on the activation of PPAR-γ in macrophages. We showed that 15(S)-HETE modifies peritoneal macrophage population balance, likely by promoting the differentiation of Small Peritoneal Macrophages (SPM) into Large Peritoneal Macrophages (LPMs). These LPMs display a phenotype which contributes to the increase of effector/regulatory T lymphocyte ratio in tumor ascites, and thus counteracts tumor-induced immunosuppression. Finally, in the third part of our work, the analysis of circulating blood monocytes in ovarian adenocarcinoma patients revealed a strong increase in the proportion of the « intermediate » subset (CD14high CD16+), usually poorly represented in healthy subjects. Interestingly, we demonstrated a positive correlation between a high proportion of intermediate blood monocytes and the presence of an immunosuppressive microenvironment in the tumor ascites of these patients (↗ Tregs, TAMS CD163high CD206high CCR2high CD86low and ↘ NK and CD8 + cytotoxic). In addition, we showed a positive correlation between the expansion of these intermediate monocytes and tumor development within the peritoneum. Together, these data highlight the role of blood monocytes as a predictive signature of immune status and tumor development within the peritoneum in patients with ovarian cancer
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Roberts, Mark G. „Investigating the Effects of Nucleosome Remodeling Factor Knockdown on Anti-Tumor Immunity“. VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4285.
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The nucleosome remodeling factor (NURF) is a chromatin remodeling complex involved in early animal development and is implicated in a number of cancers. In previous work, knockdown of NURF’s largest subunit, BPTF, resulted in diminished tumor growth in mouse cancer cell lines. Other studies in our lab demonstrated increased activation of T-lymphocytes into BPTF KD tumors. In order to examine if this approach has any therapeutic potential, this work investigates the effects of BPTF knockdown in established tumors by using recombinant adenoviruses (rAd), as well as observe the way the immune system interacts with BPTF knockdown cells, both in vivo by flow cytometry and in culture with cytotoxicity assays.
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McLarnon, Andrew. „Cellular mechanisms of alloreactive immunity following stem cell transplantation“. Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/3064/.
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Allogeneic stem cell transplantation is associated with a powerful T cell-mediated ‘graft-versus-leukaemia’ (GvL) effect and also ‘graft-versus-host disease’ (GvHD). Developing therapies to improve survival relies on greater understanding of these responses in order to enhance GvL and suppress GvHD. To gain an increased understanding of the mechanisms of GvHD I measured frequencies of Th1, Th17 and Treg subsets in the blood of 32 GvHD patients (during and outside of disease episodes) and in 21 patients who did not suffer GvHD. No associations between T cell subset frequencies or serum cytokine concentrations and incidence of GvHD were evident. My GvL work addressed whether T cell responses to cancer/testis antigens (CTAg) could be detected in a cohort of 41 patients who had undergone allogeneic stem cell transplantation for the management of acute myeloid leukaemia and multiple myeloma. CTAg-specific CD8+ T cell immune responses were observed within peripheral blood of five patients, with an average magnitude of 0.045% of the CD8+ T cell repertoire. T cell immunity was focussed against peptides derived from MAGE proteins and was increased within the bone marrow. These immune responses are likely to contribute to tumour eradication following transplantation and represent a potential novel mechanism for GvL.
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Millar, David George. „The role of idiotype-specific immunity in antigen receptor diversity“. Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/1520/.
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Lymphocytes express antigen receptors which are formed by re-arrangement of gene segments. Mutations acquired during this process, predominantly in the complementarity determining regions (CDRs), result in generation of non-germline sequences. Through analysing the CDR3 sequence, this study attempts to determine whether editing of the lymphocyte repertoire is present in an HLA-dependant manner. Data presented demonstrates a decrease frequency of CDR3-derived HLA-A2 binding peptides in HLA-A2+ donors (0.03% (SYFPEITHI) and 0.35% (BIMAS)) compared with HLA-A2- donors (0.24% (SYFPEITHI, p=0.01) and 0.54% (BIMAS, p=0.19)). Trends similar to those seen in HLA-A2 were observed in other HLA alleles as well suggesting that there may be a process by which potentially dangerous B cell populations are edited from the B cell repertoire. Similar analysis of the TCR CDR3 did not reveal any such process in all of the HLA alleles tested suggesting that there is no immunoediting of the T cell repertoire. Simultaneously, this study attempts to determine the processing and presentation of CDR3-derived peptides at the cell surface using lymphocyte antigen receptor models containing CDR3-encoded viral epitopes. The apparent presence of these peptides on the cell surface leads to the hypothesis that antibodies enter the antigen processing pathway and potentially deliver an immunogenic peptide to a target cell. Using antibodies specific for B cells, this study has shown that cells labelled with an antibody-peptide complex are targeted and lysed by cytotoxic CD4+ T cells in a peptide-specific manner. The use of such technology in antibody immunotherapy may be of considerable therapeutic benefit.
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Sabbah, Shereen. „T cell immunity to Kaposi’s sarcoma-associated herpesvirus latent proteins“. Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3273/.
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T cell immunity is important for the control of Kaposi’s sarcoma-associated herpesvirus (KSHV) disease, yet little is known about KSHV-specific immunity in healthy donors. Screening PBMCs from such donors by ELISpot analysis identified weak responses to the KSHV latent antigens; antigens expressed in the virus associated pathologies. We generated T cell clones to the latent proteins LANA and vFLIP and determined whether they recognised target cells. CD8+ clones poorly recognised targets expressing vFLIP or LANA, through mechanisms which reduce target protein synthesis: vFLIP used rare codons in the mRNA encoding this protein, while deleting the acidic repeat of LANA increased its recognition. We then examined whether LANA-specific CD4+ T cells recognised B cells expressing or fed LANA protein. These were recognised, however most KSHV-infected cell lines, in the form of primary effusion lymphoma (PEL) lines, were not. PELs express vIRF3 which inhibits promoter function of the HLA class II transactivator CIITA. Expressing CIITA from a different promoter restored CD4+ T cell recognition of PELs. This study suggests CD8 recognition of the latent antigens tested is inefficient due to the innate properties of the targets but that CD4 T cells can effectively recognise targets if the immune evasion mechanisms are bypassed.
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Pallan, Lalit. „Investigating T cell immunity against the oncogenic Merkel cell polyomavirus“. Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7165/.
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Merkel cell polyomavirus (MCV) is a causative factor in Merkel cell cancer (MCC). This aggressive skin maligrancy is associated with UV-light exposure, ageing or immunosuppression, implying immune constraint of MCC development. We examined immune control over MCV in MCC patients by comparing immune parameters with donor groups who share risk factors alongside healthy controls. This showed MCC patients had frequent and strong MCV antibody responses but no differences in responses to other polyomaviruses suggesting no general defect in humoral immunity to these viruses. MCC patients had lower frequencies of B-cells while T-cells from patients with active disease proliferated relatively poorly. Quantifying peripheral T-cell responses to the large- and small T-antigens in patient groups and healthy donors by ELISpot showed that like with other polyomaviruses, responses were weak. Novel epitopes were identified by establishing T antigenipecific CD4 and CD8 T-cell clones from healthy donors which recognised antigen expressing cells. However MCC tumours and lines were found to have low levels of surface HLA Class I and Class II and could poorly process and present epitope to T-cells. Consistent with this, preliminary experiments showed that small-T inhibited epitope presentation suggesting that small-T function must be inhibited for efficient T cell targeting of infected cells.
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Williams, Marc Adrian. „A study of granulocyte-macrophage colony stimulating factor and the immunological function of the monocyte against malignancy and infection“. Thesis, Queen Mary, University of London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367835.
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Ahmed, Jahangir. „Optimisation of the Lister strain of vaccinia virus for use as an anticancer immunotherapeutic agent“. Thesis, Queen Mary, University of London, 2015. http://qmro.qmul.ac.uk/xmlui/handle/123456789/9519.
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The premise of this project was to engineer a novel viral platform with the capacity to enhance antitumour immunity. To this effect, the N1L gene was disrupted in a Lister strain vaccinia viral backbone that had previously been engineered to be tumour selective (VVL15ΔN1L) and armed with transgenes encoding murine and human versions of GMCSF and IL12. In vitro, they retained potency for infecting, replicating in and killing a panel of murine, Syrian hamster and human cancer cells; all viruses were able to express their transgenes to detectable levels upon infection of every tumour cell line. In comparison to the parental virus (VVL15), VVL15ΔN1L administration into immune competent in vivo tumour models (of pancreatic and lung cancer) led to enhanced intratumour (IT) infiltration of neutrophils as well as markedly elevated circulating numbers of natural killer (NK) cells. VVL15ΔN1L also enhanced the tumour infiltration of CD8+ cells. Functional immunoassays and flow cytometric analysis of T cells provided evidence of enhanced tumour specific adaptive immunity. In comparison to VVL15, IT VVL15ΔN1L significantly reduced the growth of subcutaneously implanted syngeneic pancreatic tumours. This effect was predominantly due to cytotoxic lymphocytes, evidenced by the complete abrogation of efficacy upon repeating the experiment in mice that had been depleted of CD8+ cells. A similar treatment schedule reduced the formation of lung metastases from a primary spontaneously metastasising syngeneic lung cancer model; and translated into prolonged short-term post-operative survival when used as neoadjuvant to surgical resection. Efficacy in this context was contrastingly, due to an elevation in systemic NK cells; concurrent depletion of NK cells (but not CD4+ or CD8+ cells) completely abrogated the survival advantage. The IL12 transgene armed recombinant was the most effective antitumour therapeutic. Its IT administration into pancreatic tumours led to complete tumour eradication in over 80% of tumour bearing mice and was effective in slowing the growth of other aggressive flank tumours. Neoadjuvant administration of VVL15ΔN1L-mIL12 into metastatic lung cancers dramatically prolonged long-term post-surgical survival, with apparent cure of 88% of mice.
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Leppänen, J. (Joni). „The role of hypoxia, innate immunity receptors and stromal response in pancreatic cancer“. Doctoral thesis, Oulun yliopisto, 2019. http://urn.fi/urn:isbn:9789526221809.
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Abstract Pancreatic cancer remains one of the deadliest malignancies, with dismal prognosis. Pancreatic cancer arises from precursor lesions called pancreatic intraepithelial neoplasia. Toll-like receptors (TLR) are receptors of the innate immunity responsible for initiating immune responses against invading pathogens. Their involvement in cancer progression is becoming evident. Hypoxia is a typical characteristic of pancreatic cancer and linked to poor prognosis. Typically, pancreatic cancer has an abundant desmoplastic stroma that contributes to the hypoxia and poor delivery of anti-tumor drugs to the cancer cells. Tenascin-C and fibronectin are proteins of the extracellular matrix. They are involved in normal organ development, but in recent years, their involvement in various cancers has become evident. This thesis examined the involvement of Toll-like receptors, hypoxia markers HIF-1alpha and Carbonic anhydrase 9 (CAIX) as well as stromal markers tenascin-C and fibronectin in pancreatic cancer. Furthermore, the prognostic effect of each protein was evaluated. The material consisted of whole section tissue samples of surgically treated patients with pancreatic ductal adenocarcinoma. The expression of the proteins was evaluated using immunohistochemical stainings. TLR, HIF-1alpha, CAIX, tenascin-C and fibronectin were all abundantly expressed in pancreatic cancer. High TLR9 associated with improved prognosis while weak HIF-1alpha indicated poor prognosis. In a subgroup analysis consisting of only T1 and T2 tumors, high tenascin-C associated with poor prognosis. There was no significant correlation between TLR and hypoxia marker expression. Based on these results, TLR2, TLR4 and TLR9 are expressed in pancreatic cancer, and high TLR9 associates with improved survival of the patients. Weak HIF-1alpha associated with poor prognosis, suggesting that other factors than hypoxia might be involved in the regulation of HIF-1alpha expression. Tenascin-C and fibronectin are not associated with patient prognosis in pancreatic cancerTiivistelmä Haimasyövällä on kaikista syövistä yksi huonoimmista ennusteista. Haimasyöpä kehittyy tiehyidensisäisistä muutoksista, joita kutsutaan englanninkielisellä nimellä pancreatic intraepithelial neoplasia (PanIN). Tollin kaltaiset reseptorit (TLR) ovat luontaisen immuniteetin reseptoreja, ja niiden tehtävä on aloittaa elimistön puolustusvaste tunkeutuvia taudinaiheuttajia vastaan. Tollin kaltaisten reseptorien osuus on osoitettu eri syövissä. Hypoksia on tyypillistä haimasyövälle, ja se on yleensä yhteydessä huonontuneeseen ennusteen. Tyypillisesti haimasyövällä on voimakas sidekudosreaktio, joka osaltaan lisää kasvaimen hapenpuutetta ja vaikeuttaa sytostaattien kulkeutumista syöpäsoluihin. Tenaskiini ja fibronektiini ovat solunulkoisen tilan proteiineja, jotka osallistuvat normaaliin elimistön kehitykseen. Viime aikoina niillä on huomattu olevan osuutta myös erilaisten syöpien kehittymiseen. Tässä väitöskirjassa on tutkittu Tollin kaltaisten reseptorien, hypoksiamerkkiaineiden HIF-1alpha ja hiilihappoanhydraasi 9 (CAIX) sekä sidekudosmerkkiaineiden tenaskiini ja fibronektiini ilmentymistä haimasyövässä. Lisäksi tutkimuksessa selvitettiin näiden proteiinien osuutta haimasyövän ennusteeseen. Tutkimuksen materiaali koostuu haimasyöpäpotilaiden syöpäkudosnäytteistä. Näytteinä käytettiin kokoleikenäytteitä. Näytteille tehtiin immunohistokemialliset värjäykset, joista eri proteiinien ilmentymistä arvioitiin. Tollin kaltaiset reseptorit, HIF-1alpha, CAIX, tenaskiini ja fibronektiini ilmenivät kaikki haimasyövässä. Korkea TLR9 oli yhteydessä parantuneeseen ennusteeseen, kun taas heikko HIF-1alpha oli yhteydessä huonontuneeseen ennusteeseen. Huomioitaessa vain T1- ja T2-kasvaimet korkea tenaskiini oli yhteydessä huonontuneeseen ennusteeseen. Tollin kaltaisten reseptorien ja hypoksiamerkkiaineiden välillä ei ollut merkittävää yhteyttä. Tulosten perusteella haimasyövässä on runsaasti Tollin kaltaisia reseptoreita, ja korkea TLR9 on yhteydessä parantuneeseen ennusteeseen. Matala HIF-1alpha on yhteydessä huonoon ennusteeseen. Tenaskiinilla ja fibronektiinilla ei ole vaikutusta potilaiden ennusteeseen
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Bergin, Stephen Michael. „Hypothalamic brain-derived neurotrophic factor regulates lymphocyte immunity, energy balance, and cancer progression“. The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487669797216355.
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Rothschilds, Adrienne Marie. „Engineering protein-based modulators of allergic, temporal, and checkpoint blockade anti-cancer immunity“. Thesis, Massachusetts Institute of Technology, 2019. https://hdl.handle.net/1721.1/123064.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2019Cataloged from PDF version of thesis.
Includes bibliographical references (pages 128-137).
Effective cancer treatment of the future requires incorporating diverse and innovative aspects of immunity to fight against cancer, accounting for pharmacokinetic and temporal barriers of therapeutics, and engineering approaches to understand and improve upon current immunotherapies. This thesis addresses these challenges in three projects utilizing the Wittrup Lab's quantitative, engineering approach to protein-based cancer immunotherapy. In the first project, I attempted to harness the potency of allergic reactions against cancer by designing IgE class antibodies against two mouse tumor antigens and comparing them with traditional IgG antibodies. These IgE antibodies elicited modest or no tumor control, and limited efficacy could be due to fast pharmacokinetic clearance, absence of human-like allergic effector cells in mice, or tumor-suppressive effects from mast cells responding to IgE.
The second project described in this thesis focused on synchronizing combination immunotherapies with the temporal progression of the anti-cancer immune response. In this work, anti-tumor antibodies were combined with the cytokines interleukin 2 (IL2) and interferon alpha (IFNa). The order of administration of these therapies decoupled strong efficacy from dose-limiting toxicity in two tumor models. Given before IFN[alpha], IL2 activated natural killer cells and heightened their responsiveness to subsequent IFN[alpha], which was ultimately toxic and unnecessary for therapeutic efficacy. This project's proof of concept that efficacy and toxicity could be unlinked in immunotherapy began to establish a framework to use for rational combination therapy treatment schedule design, with the goal of treating with each agent when that piece of the immune system is active.
Finally, the third project used the Wittrup Lab's system of yeast surface display to engineer novel antibodies against the checkpoint blockade target cytotoxic T lymphocyte associated protein 4 (CTLA-4) as tools to improve understanding of the anti-CTLA-4 mechanism of action against cancer. Although the first wave of antibodies made had favorable characteristics against CTLA-4 as a soluble target, they bound a CTLA-4 epitope too close to the cell surface and so could not be used for therapeutic studies. Next generation sequencing on the yeast libraries identified alternative CTLA-4 binding antibody sequences, and these will be tested in future mechanistic and therapeutic studies.
by Adrienne Marie Rothschilds.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Biological Engineering
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Mansi, Laura. „Intégration de l’analyse de l’immunomodulation induite par les inhibiteurs de mTOR dans leur développement en cancérologie“. Thesis, Bourgogne Franche-Comté, 2017. http://www.theses.fr/2017UBFCE012.
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Le rôle central de la voie mTOR (mammalian Target Of Rapamycin) dans l’homéostasie cellulaire suscite un réel intérêt dans de nombreux domaines thérapeutiques. Les inhibiteurs de mTOR (mTORi) sont utilisés en prévention du rejet de greffe par leur action d’inhibition de l’activation lymphocytaire T et l’induction de lymphocytes T régulateurs (Treg). En cancérologie, les mTORi sont utilisés pour leur action anti-proliférative et anti-angiogénique. Cependant, l’efficacité clinique de ces traitements reste modeste. Bien que des mécanismes de résistance aux mTORi intrinsèques à la cellule tumorale ont été identifiés, leur impact sur le système immunitaire émerge comme un facteur essentiel dans leur efficacité. Notre hypothèse est donc que l’efficacité anti-tumorale des mTORi serait également liée à la modulation de l’immunité anti-tumorale induite par ces traitements.Nous avons réalisé un immunomonitoring, du taux de Treg et de la réponse lymphocytaire Th1 anti-tumorale au sein d’une cohorte prospective de patients atteints de cancer rénal métastatique traités par éverolimus (mTORi).Nous avons observé une augmentation des Treg et de leur fonction suppressive à partir du 2ème mois de traitement dans la quasi-totalité des patients. Paradoxalement, une augmentation des réponses Th1 anti-tumorales a également été observée chez ces patients. Au moment de la progression tumorale, la majorité des patients ont présenté une forte augmentation des Treg associée à une perte de la réponse Th1. Ainsi, nous avons pu définir différents profils immunitaires basés sur la modulation de ces deux paramètres. Les patients présentant une diminution précoce des Treg associée à une augmentation de la réponse Th1 avaient une meilleure survie sans progression par rapport aux autres patients (13.2 vs 4 mois p= 0.02). De façon consistante, cette immunomodulation a été confirmée chez des patients atteints de tumeur neuroendocrine traités par éverolimus. De plus, l’impact du traitement sur les Treg et la réponse Th1 n’était pas influencé par la pharmacocinétique du médicament. Par la suite, nous avons étudié in vivo, chez des souris porteuses de différentes tumeurs, l’impact des mTORi sur la réponse immunitaire anti-tumorale. Comme chez les patients, nous avons observé une augmentation des Treg chez les souris traitées par mTORi. Ainsi, l’utilisation d’anticorps déplétants les Treg ou de souris transgéniques ont permis de démontrer le rôle délétère des Treg sur l’efficacité anti-tumorale des mTORi. Ces résultats suggèrent fortement que les mTORi ont un double effet sur le système immunitaire dans un contexte tumoral, un premier néfaste par l’induction d’un environnement immunosuppresseur et le second positif par l’augmentation d’une réponse Th1 anti-tumorale.Dans un deuxième travail, nous avons exploré l’effet positif des mTORi sur le système immunitaire afin d’optimiser les immunothérapies anti-tumorales. Nous avons montré que l’administration de temsirolimus (mTORi) améliore l’efficacité anti-tumorale d’un vaccin thérapeutique chez la souris. L’effet synergique de cette combinaison était lié à une augmentation de l’infiltration tumorale des LT CD8 anti-tumoraux de phénotype centro-mémoire. L’efficacité de cette combinaison a été nettement améliorée par l’addition d’un antagoniste de CCR4 permettant d’éliminer les Treg induits par le temsirolimus.En conclusion, les mTORi demeurent une stratégie prometteuse en cancérologie malgré la réduction de leur utilisation due à l’arrivée des nouvelles immunothérapies, comme les checkpoints inhibiteurs (notamment dans le cancer du rein) et d’autres thérapies ciblées (inhibiteurs de cycline dans le cancer du sein). En revanche, le futur développement des mTORi devra s’appuyer sur des biomarqueurs prenant en compte l’impact de ces traitements sur le système immunitaire et sur des combinaisons thérapeutiques notamment avec les immunothérapiesThe key role of the mTOR (mammalian Target of Rapamycin) pathway in cellular homeostasis raises a real interest in many therapeutics areas. Inhibitors of mTOR (mTORi) are used for graft rejection prevention to inhibit the T lymphocyte (LT) activation and induce regulatory T cells (LTreg). In cancerology, they are used for their antiproliferative and antiangiogenic actions. However, the clinical efficacy of those treatments is low. Although several mTORi resistance mechanisms linked to the tumor cell have been identified, their impact on the immune system appears as a key factor in their efficiency. Thus, our hypothesis is that the clinical efficacy of mTORi could also be dependent of an anti-tumoral immunity modulation resulting from those treatments.We performed an immunomonitoring of the Treg rate and the tumor specific Th1 anti-tumor response among a prospective cohort of patients with a metastatic renal carcinoma treated by everolimus (mTORi). We observed that the Treg rate and the suppressive function increase after the second month of treatment for almost all the patients. Paradoxically, an increase of the Th1 anti-tumoral response has also been observed for these patients. At disease progression, a majority of the patients has shown an important increase of Treg with a decrease of the Th1 response. Thus, we have been able to define different immune profiles based on the modulation of these two parameters. Progression free survival of patients with an earlier decrease of Treg and an increase of Th1 response was significantly longer compared to other patients (13.2 vs 4 months p=0.02). This immunomodulation has been consistently confirmed with patients affected by neuroendocrine tumor and treated with everolimus. The treatment impact on Treg and the Th1 response was not related to the pharmacokinetic of the drug. Thereafter, we have studied in vivo the impact of mTORi on the anti-tumoral immune response with mice affected by different tumors. We have observed the same increase of Treg in mice treated with mTORi as the increase observed in the patients. Thus, using antibodies depleting the Treg or transgenic mice allowed us to confirm the deleterious role of Treg on the anti-tumor mTORi efficacy. Those results strongly suggest that mTORi have a double effect on the immune system, a harmful impact by the induction of an immunosuppressive environment and a positive impact by the increase of the anti-tumor Th1 response.In a second time, we have studied the positive effect of mTORi on the immune system in order to optimize the anti-tumoral immunotherapies. We have shown that the administration of temsirolimus (mTORi) improves the anti-tumoral efficiency of a therapeutic vaccination on mice. Indeed, the synergic effect of this combination is tied with an augmentation of tumor infiltrate anti-tumor T CD8 with a central memory phenotype. The efficiency of this combination has been greatly improved by the addition of an antagonist CCR4 allowing the elimination of Treg generated by temsirolimus.In conclusion, mTORi remain a promising strategy in cancerology even if their use is likely to be reduced as new immunotherapies such as checkpoint inhibitors (renal carcinoma) or other targeted therapies (cycline dependent kinase inhibitors in breast cancer) appeared. In the future, the development of mTORi must integrate biomarkers taking into account the impact of these treatments on the immune system, and therapeutic combination such as the immunotherapy
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Janho, Dit Hreich Serena. „Rôle de l'immunomodulateur P2RX7 dans le cancer et la fibrose pulmonaire“. Electronic Thesis or Diss., Université Côte d'Azur, 2022. http://www.theses.fr/2022COAZ6020.
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Malgré de nouvelles connaissances biologiques et des avancées thérapeutiques récentes, les cancers du poumon sont encore la première cause de décès liés au cancer alors que la fibrose pulmonaire idiopathique est incurable. Il est donc urgent d'élaborer de nouvelles approches pour aider les patients atteins de ces pathologies.P2RX7 est un récepteur canal activé par de fortes concentrations d'ATP extracellulaire (ATPe), concentrations retrouvées dans les tissus tumoraux et fibreux. Il joue un rôle majeur dans la modulation du système immunitaire par sa capacité à activer l'inflammasome NLRP3 et à libérer les cytokines IL-1β et IL-18. L'activation de P2RX7 conduit aussi à la formation de macropores à la membrane pouvant induire la mort cellulaire. Ces observations font de P2RX7 un récepteur aux capacités immunomodulatrices et antitumorales qui peuvent être exploitées. Ainsi, une collaboration avec des chimistes a permis de synthétiser une molécule nommée HEI3090 que j'ai utilisé pendant ma thèse.Durant la première partie de ma thèse, j'ai étudié l'effet de HEI3090 dans le contrôle de la croissance tumorale en utilisant deux modèles murins immunocompétents de cancer du poumon. J'ai d'abord identifié HEI3090 comme un modulateur positif de P2RX7 qui nécessite la présence d'ATPe pour potentialiser ses activités. J'ai ensuite montré que HEI3090 inhibe la croissance des tumeurs en réactivant une réponse immunitaire antitumorale, cet effet repose sur la production d'IL-18 par les cellules dendritiques. L'augmentation d'IL-18 se fait de façon NLRP3-dépendante et favorise le recrutement et la cytotoxicité des lymphocytes T CD4+ et NK ainsi que l'immunogénicité de la tumeur. De ce fait, la combinaison de HEI3090 avec des anti-PD-1 guérit 80% des souris dans le modèle de tumeurs transplantées et réduit de 60% la charge tumorale dans le modèle de carcinogenèse in situ. De plus, ces souris sont protégées d'un rechallenge tumoral grâce à la mise en place d'une réponse immunitaire mémoire CD8-dépendante. Ces résultats mettent en évidence que l'activation de P2RX7 constitue une stratégie thérapeutique prometteuse dans les cancers du poumon.Durant la deuxième partie de ma thèse, j'ai étudié la capacité de HEI3090 à contrôler le développement de fibroses pulmonaires. J'ai d'abord montré que l'expression de la voie P2RX7/IL-18/IFN-γ est diminuée chez les patients atteints de fibrose pulmonaire idiopathique (FPI), suggérant le potentiel antifibrotique de P2RX7. Ensuite, grâce au modèle murin de fibrose pulmonaire induite par inhalation de bléomycine, j'ai montré que HEI3090 empêche le développement de fibroses pulmonaires. HEI3090 cible la voie P2RX7/NLRP3/IL-18 dans les cellules immunitaires et favorise un profil immunitaire antifibrotique caractérisé par une forte production d'IFN-γ par les lymphocytes T, une diminution de production de TGFβ ainsi qu'une réduction du nombre de cellules inflammatoires. J'ai également montré que les niveaux élevés d'IL-18 plasmatique chez les patients FPI semblent prédire une meilleure survie des patients. L'ensemble de ces résultats suggère que P2RX7 est une nouvelle stratégie thérapeutique dans la FPI et nous permet de proposer que le niveau d'IL-18 plasmatique pourrait constituer un biomarqueur prédictif dans la FPI.Enfin, j'ai développé un protocole permettant d'étudier l'activation de P2RX7 in vivo basé sur la formation de macropores dans des souris sauvages et p2rx7-/-. Ce protocole permet d'étudier l'effet in vivo de molécules ciblant P2RX7, dont HEI3090. Actuellement, ces molécules ne sont étudiées qu'in vitro ou de façon indirecte in vivo. De plus, ce protocole permet d'identifier la cellule ciblée et de déterminer les doses à administrer pour une meilleure efficacité.L'ensemble de ce travail a permis de mettre en avant une stratégie thérapeutique dans deux pathologies pulmonaires mais également d'identifier un potentiel biomarqueur prédictif qui est l'IL-18Despite new findings and recent therapeutic progress, lung cancer is still the leading cause of cancer-related deaths whereas idiopathic pulmonary fibrosis (IPF) is still incurable. It is therefore urgent to find new strategies to help patients affected by these pathologies.P2RX7 is a canal receptor activated by high levels of extracellular ATP (eATP). Such levels of eATP are found in tumor and fibrotic tissues. P2RX7 plays a major role in modulating the immune response since it induces the activation of the NLRP3 inflammasome and the release of IL-1β and IL-18. Activation of P2RX7 allows the opening of macropores at the plasma membrane that could lead to cell death. Therefore, P2RX7 has immunomodulatory and antitumoral proprieties that could be boosted. Therefore, the team collaborated with chemists to synthetize a molecule named HEI3090 which I used during my PhD.During the first part of my PhD, I studied the impact of HEI3090 on tumor growth using two immunocompetent mouse models of lung cancer. I first identified HEI3090 as a positive modulator of P2RX7 that requires the presence of eATP to enhance P2RX7's activities. Then, I showed that HEI3090 inhibits lung tumor growth by reactivating an antitumor immune response that relies on IL-18 release by dendritic cells. HEI3090 enhances IL-18 release in a NLRP3-dependant manner and favors the recruitment and cytotoxicity of tumor infiltrating CD4+ T cells and NK cells as well as the enhancement of tumor immunogenicity. Hence, the combination of HEI3090 with anti-PD-1 cures 80% of mice in the subcutaneous mouse model and reduces the tumor burden by 60% in the in situ carcinogenesis mouse model. Moreover, cured mice were protected from a tumor rechallenge in a CD8-dependant manner. These results highlight the activation of P2RX7 as a therapeutic strategy in the treatment of lung cancer.During the second part of my PhD, I studied the ability of HEI3090 to control lung fibrosis progression. I first showed that the P2XR7/IL-18/IFN-γ pathway is downregulated in patients with IPF suggesting the antifibrotic potential of P2RX7. Using the bleomycin induced lung fibrosis mouse model, I showed that HEI3090 inhibits lung fibrosis progression by targeting the P2RX7/NLRP3/IL-18 pathway in immune cells. HEI3090 favors an antifibrotic immune profile since it enhances the production of IFN-γ by T cells, reduces TGFβ production as well as reduces the number of proinflammatory cells in the lung. I also showed that high levels of plasmatic IL-18 in IPF patients seem to predict a better survival. These findings suggest that targeting P2RX7 is a new therapeutic strategy in IPF. We also propose that plasmatic IL-18 levels could be a predictive biomarker in this disease.Lastly, I set up a protocol to evaluate the in vivo activation of P2RX7. The protocol is based on studying the macropore opening in wild type mice, which was further validated in p2rx7-/- mice. The ultimate goal of the protocol is to study the impact of molecules targeting P2RX7, notably HEI3090. Indeed, such molecules are currently studied in vitro or indirectly in vivo. Moreover, the protocol allows to identify the cell type targeted by such molecules as well as to define a therapeutic dose for better efficacy.Overall, this work highlights a therapeutic strategy in two lung pathologies and identifies a potential new predictive biomarker that is IL-18
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Sfondrini, Lucia. „Enhancement of anti-tumour immunity by transduction with a Mycobacterium tuberculosis gene“. Thesis, Open University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342892.
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Peng, Judy Chun-Ju. „Optimization of Dendritic cells for cancer immunotherapy /“. [St. Lucia, Qld.], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18443.pdf.
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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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Bingula, Rea. „Non-small cell lung cancer, immunity and microbiota : laying ground for the gut-lung-lung cancer axis in human subjects“. Thesis, Université Clermont Auvergne (2017-2020), 2019. http://www.theses.fr/2019CLFAS009.
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Le cancer du poumon est la principale cause de décès par cancer dans le monde. En dépit de la variété de traitements disponibles, tels que la chirurgie, la chimiothérapie, la radiothérapie et l’immunothérapie, la survie moyenne à 5 ans est de 60 %. L’une des raisons sous-jacente est une très grande variabilité de réponse au traitement, expliquée par les antécédents génétiques du patient et depuis peu par son microbiote. Le terme « microbiote » regroupe les bactéries, les archées, les champignons, les virus et les protistes qui colonisent notre organisme. Des études utilisant des modèles animaux montrent que le microbiote intestinal joue un rôle crucial dans la réponse de l’hôte au traitement, via la stimulation du système immunitaire. Dans ce contexte, plusieurs « axes de communication » entre le site intestinal et les sites tumoraux distaux commencent à émerger, y compris l’axe « intestin-poumon ». Cependant, le microbiote pulmonaire, qui pourrait directement influencer la réponse tumorale et interagir avec le microbiote intestinal, est pour l’heure peu caractérisé. Afin de développer cette idée d’un axe « intestin, poumon et cancer du poumon », nous avons inclus dans notre étude 18 patients atteints d’un cancer du poumon non à petites cellules (CBNPC) admissibles à la chirurgie. Nous avons analysé leurs microbiotes par séquençage à haut débit à partir de quatre échantillons différents de poumon (tissu sain, tissus péritumoral et tumoral et fluide de lavage broncho-alvéolaire LBA) mais également à partir d’échantillons de salive et de fèces. Nous avons également analysé plusieurs marqueurs immunitaires (infiltration lymphocytaire des tumeurs, profils Th et neutrophiles, cytokines dans le LBA et le sang), des marqueurs inflammatoires et enfin les acides gras à chaînes courtes dans les fèces. Une caractérisation détaillée de ces quatre types d’échantillons de poumons nous a permis de montrer que le microbiote du LBA présente une communauté nettement distincte de celle du tissu pulmonaire. Les tumeurs des lobes inférieurs prédisant le plus mauvais pronostic, nous avons décidé d’étudier le lien entre l’emplacement des tumeurs et la composition du microbiote. Les microbiotes du tissu péritumoral et du LBA ont été identifiés comme étant les plus impactés en terme d’abondance et de diversité ; la tumeur est quant à elle moins impactée. Cependant nous avons observé que le phylum des Firmicutes, décrit comme étant élevé dans les maladies pulmonaires obstructives chroniques, est plus abondant dans le microbiote des lobes inférieurs du poumon. Par conséquent, nous pouvons émettre l’hypothèse que l’augmentation des Firmicutes et les variations importantes du microbiote dans le tissu péritumoral pourraient être associés à une agressivité accrue des tumeurs du lobe inférieur. Nous avons ensuite démontré que la présence de ganglions lymphatiques (GL) métastatiques, marqueur d’un pronostic négatif dans le NSCLC, influence considérablement le microbiote local de par le profil respiratoire du tissu. Nous avons en effet observé que les bactéries anaérobies étaient plus abondantes dans les tumeurs en présence de LN métastatiques. Les bactéries aérobies sont quant à elles plus représentées dans les tumeurs sans GL métastatiques. Nous avons cependant observé la situation inverse dans les tissus extratumoraux. L’hypothèse avancée est celle d’une migration bactérienne en fonction des préférences de conditions de croissance, directement liées aux caractéristiques de la tumeur. Ceci nous permet de proposer plusieurs biomarqueurs pour la détection de GL métastatique, facilitant ainsi leur détection sans imposer de biopsie. Enfin, nous montrons que le microbiote du LBA est d’avantage associé à la réponse immunitaire locale et est indépendant de la présence de GL métastatique. Les recherches à venir porteront sur l’exploration de l’interaction entre le microbiote pulmonaire, l’immunité systémique et le microbiote intestinalLung cancer is the main cause of death by cancer worldwide. Despite the variety of available treatments, including surgery, chemotherapy, radiotherapy, and immune therapy, the average 5-year survival is 60%. One of the underlying reasons is a very high variability in patients’ susceptibility to treatment, explained by genetic background and since recently – our microbiota. The term microbiota includes bacteria, archaea, fungi, viruses and protists that inhabit our organism. The studies in animal models show that the gut microbiota (focused on bacteria) has a crucial role in host’s responsiveness to therapy through the stimulation of immune system. In this light, several “communication axes” between the gut and distal tumour sites have started to develop, including the “gut-lung” axis. However, the resident microbiota in the lungs that could directly influence the tumour response and interact with the gut microbiota has been scarcely characterised. To enable further development of the idea of the “gut-lung-lung cancer” axis, we included 18 non-small cell lung cancer (NSCLC) patients eligible for surgery and analysed the microbiota from four different lung samples (non-malignant, peritumoural and tumour tissue and bronchoalveolar lavage fluid; BAL), saliva and faeces by high-throughput sequencing. We also analysed several immune markers, as lymphocytic tumour infiltrate, Th and neutrophil profiles and cytokines in BAL and blood, and inflammatory markers in faeces along with short-chain fatty acids. Focusing first on the lungs, we show that BAL microbiota represents a significantly distinct community compared to lung tissue microbiota by providing detailed characterisation of the four different lung samples. Since tumours in lower lobes are reported as the ones with the worse prognosis, we investigated how the lobe location affected the microbiota composition. Peritumoural tissue and BAL microbiota were identified as the most affected in both abundance and diversity, and tumour as the least affected. However, phylum Firmicutes, previously reported as elevated in chronic obstructive pulmonary disease compared to controls, was found more abundant in microbiota from lower lung lobes. Therefore, we propose that both increase in Firmicutes and extensive changes in peritumoural tissue could be associated to increased aggressiveness of the lower lobe tumours. Next, we show that the presence of metastatic lymph nodes (LN), negative prognostic marker in NSCLC, significantly influence the local tissue microbiota in relation to its respiratory profile. We reported that anaerobic bacteria were more abundant within the tumour in the presence of metastatic LN, and aerobic bacteria within the one without it. Moreover, exactly inverse was observed for the same bacteria in extratumoural tissues. Along with migratory hypothesis depending on the bacterial preference for growth conditions shaped by tumour’s features, we propose several biomarkers for detection of metastatic LN that might facilitate their detection without imposing LN biopsy. Finally, we showed that BAL microbiota is the most associated to the local immune response and independent of the presence of metastatic LN. Future research will focus on the exploration of the interaction between the lung microbiota, systemic immunity and the gut microbiota
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O'Hara, Richard James. „Interleukin-12 a pivotal cytokine in cell mediated immunity : the role in colorectal cancer“. Thesis, University of Hull, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395426.
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Moynihan, Kelly D. (Kelly Dare). „Engineering immunity : enhancing T Cell vaccines and combination immunotherapies for the treatment of cancer“. Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/113960.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2017.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 127-140).
Checkpoint blockade with antibodies against CTLA-4 or PD-1 has demonstrated that an endogenous adaptive immune response can be stimulated to elicit durable tumor regressions in metastatic cancer, but these dramatic responses are confined to a minority of patients¹-³. This outcome is likely due in part to the complex network of immunosuppressive pathways present in advanced tumors, which necessitates the development of novel therapeutics and combination immunotherapies to generate a counter-directed network of pro-immunity signals⁴-⁸. In Chapters 2 and 3 of this thesis, we describe methods for enhancing T cell priming against tumor antigens via covalent modification of molecular vaccines to enhance lymphatic drainage, serum stability, or cytosolic access to improve presentation on MHC class I. In Chapter 4, we demonstrate a combination immunotherapy that recruits a diverse set of innate and adaptive effector cells, enabling robust elimination of large tumor burdens that to my knowledge have not previously been curable by treatments relying on endogenous immunity. Maximal anti-tumor efficacy required four components: a tumor antigen targeting antibody, an extended half-life IL-2⁹, anti-ƯPD-1, and a powerful T-cell vaccine¹⁰. This combination elicited durable cures in a majority of animals, formed immunological memory in multiple transplanted tumor models, and induced sustained tumor regression in an autochthonous BRraf[superscript V600E]/Pten[superscript -/-] melanoma model. Finally, in Chapter 5, we show preliminary data on combination immunotherapies used to treat antigenically heterogeneous tumors. Taken together, these data define design criteria for enhancing the immunogenicity of molecular vaccines and elucidate essential characteristics of combination immunotherapies capable of curing a majority of tumors in experimental settings typically viewed as intractable.
"During my doctorate by the John and Fanny Hertz Foundation Fellowship (specifically the Wilson Talley Hertz Fellowship), the NSF Graduate Research Fellowship Program, and the Siebel Scholarship"--Page 141. "This thesis work was supported in part by the Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute, the US National Institutes of Health (NIH) grant CA174795, the Bridge Project partnership between the Koch Institute for Integrative Cancer Research and the Dana Farber-Harvard Cancer Center (DF-HCC), the V Foundation, the Ragon Institute, and the Howard Hughes Medical Institute"--Page 141.
by Kelly D. Moynihan.
Ph. D.
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Namjoshi, Prachi Mukund. „Th-1 Cytokine and Antibody Mediated Immunity against HER Family Expressing Breast Cancer Cells“. Kent State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=kent1461250751.
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Zhao, Junjie. „MECHANISMS OF SINGLE IG IL-1-RELATED RECEPTOR MEDIATED SUPPRESSION OF COLON TUMORIGENESIS“. Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1459761067.
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Zheng, Ying, und 鄭盈. „A complementary activation of peripheral NK cell immunity in EBV related nasopharyngeal carcinoma“. Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B34605162.
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Grandal, Rejo Beatriz. „Beyond Breast Cancer : The Interplay of Immunity, Comedications, and Comorbidities in Treatment Response and Outcomes“. Electronic Thesis or Diss., université Paris-Saclay, 2023. http://www.theses.fr/2023UPASL063.
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Le cancer a provoqué près de 10 millions de décès en 2020, il est prévu qu'il affectera presque 24,5 millions de personnes d'ici 2035 en raison des changements de mode de vie, du vieillissement et des facteurs environnementaux. Le cancer du sein (CS) est le diagnostic de cancer le plus fréquent et la première cause de mortalité oncologique chez les femmes. L'incidence du CS s'accroît avec l'âge, en parallèle avec la prévalence croissante des conditions concomitantes (comorbidités) et des prescriptions de médicaments chroniques (comédications), signalées chez environ la moitié de tous les patients atteints de cancer. L'administration de chimiothérapie avant la chirurgie (NAC) permet aux cliniciens d'évaluer la chimiosensibilité tumorale in vivo. L'objectif de cette thèse est de mener une analyse exhaustive pour étudier les relations complexes entre les lymphocytes infiltrant la tumeur (TILs), checkpoints, les déterminants génétiques, les sous-types de cancer du sein, les comédications, les comorbidités, la réponse au traitement et les résultats oncologiques chez les patients atteints de cancer du sein. Cet objectif sera atteint grâce à une étude intégrative des ensembles de données provenant de preuves du monde réel (RWE), et à une analyse post-hoc des essais contrôlés randomisés (RCTs). La première section de cette thèse offre une revue complète du paradigme dutraitement néoadjuvant dans le cancer du sein, se concentrant sur l'interconnexion de la biologie tumorale, des TILs, de la chimiosensibilité et de la survie. La section suivante cherche à étudier le rôle des comédications dans le traitement du cancer en examinant les associations entre l'utilisation des comédications, les comorbidités, l'infiltration immunitaire et la réponse au traitement. Ce chapitre vise à identifier des interactions insoupçonnées qui pourraient améliorer les résultats pour les patients en découvrant de nouvelles applications thérapeutiques pour des médicaments existants (drug repurposing). De plus, nous entreprenons une analyse approfondie des effets des médicaments concomitants prescrits régulièrement sur la survie du CS en utilisant des données du Système National des Données de Santé (SNDS) de la France. Nous nous efforçons de dessiner une carte détaillée des interactions potentielles entre les médicaments concomitants et la survie dans le contexte de la population française entière. En conclusion, le CS incarne un réseau complexe d'interactions entre la tumeur et le microenvironnement, avec de nombreux facteurs d'influence encore à élucider pleinement. Les contextes néoadjuvants et l'intégration de vastes bases de données peuvent identifier de nouvelles cibles thérapeutiques et des interactions médicamenteuses, qui sont essentielles pour faire progresser une médecine de précision sûre et rentableCancer caused almost 10 million deaths in 2020 and is predicted to affect nearly 24.5 million people by 2035 due to lifestyle changes, aging, and environmental factors. Breast cancer (BC) is the most frequent cancer diagnosis and the first cause of oncology mortality among females. The incidence of BC escalates with increasing âge, paralleling the rising prevalence of co-existing conditions (comorbidities) and chronic médication prescriptions (comedications), reported in roughly half of ail cancer patients. Administering chemotherapy prior to surgery (NAC) allows clinicians to evaluate in vivo tumor chemosensitivity. The objective of this thesis is to perform a comprehensive analysis to investigate the intricate relationships among tumor-infiltrating lymphocytes (TILs), checkpoints, genetic déterminants, breast cancer subtypes, comedications, comorbidities, treatment response, and oncological outcomes in patients with breast cancer. This objective will be achieved via an intégrative examination of datasets from real-world evidence (RWE) and a post-hoc analysis of randomized controlled trials (RCTs). The opening section of this thesis provides a comprehensive review of the neoadjuvant treatment paradigm in breast cancer, focusing on the interconnectedness of tumor biology, TILs,chemosensitivity, and survival. This research offers valuable insights into the intricate network that governs treatment outcomes. The subséquent segment seeks to study the rôle of comedications in cancer treatment by examining the associations between comedication use, comorbidities, immune infiltration, and treatment response. This chapter aims to identify unsuspected interactions that may improve patient outcomes by discovering novel therapeutic applications for existing drugs (drug repurposing). Moreover, we undertake an in-depth examination of the effects of regularly prescribed concomitant médications on BC survival using data from the French National Health Data System (SNDS). We endeavor to delineate a detailed map of potential interactions between concomitant médications and survival in the context of the entire French population. In conclusion, BC epitomizes a complex network of tumor and microenvironment interactions, with numerous influencing factors yet to be fully elucidated. Neoadjuvant settings and vast database intégration can identify novel therapeutic targets and drug-drug interactions, which are vital for advancing cost-effective, safe précision medicine
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Do, Priscilla. „Immune Attunement: Fortifying Anti-Tumor Immunity Via T Cell Co-Stimulation“. The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492568422442233.
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Bonsang-Kitzis, Hélène. „Caractérisation moléculaire et immunité des cancers du sein triple-négatifs“. Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS162.
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Le cancer du sein triple négatif (CSTN) est le sous-type de cancer du sein le plus hétérogène et le plus défavorable. La pierre angulaire du traitement de ces tumeurs repose sur la chimiothérapie systémique, de plus en plus fréquemment administrée en néoadjuvant, puisqu’aucune thérapie ciblée n’est à ce jour validée. L'obtention d'une réponse complète histologique (RCH) constitue un marqueur pronostique favorable majeur ainsi qu'un test in vivo de la sensibilité aux médicaments anti-tumoraux. L’objectif de notre travail de thèse a donc été d’apporter des éléments de compréhension de cette hétérogénéité grâce à la dissection clinique, biologique et moléculaire de ces tumeurs. Nous avons analysé les profils d'expression géniques de ces CSTN et ainsi identifié 6 sous-types moléculaires distincts avec des biologies et des pronostics différents. Cette classification s’appuie sur une méthodologie originale basée à la fois sur des outils bioinformatiques classiques associée à l’utilisation de réseaux biologiques. L’enrichissement en gènes de l'immunité issus du compartiment stromal de la tumeur représente un déterminant majeur du pronostic de ces tumeurs : une forte expression des gènes de l'immunité est associée un pronostic significativement plus favorable. Notre principale contribution repose sur une meilleure compréhension de l’immunité et de l’infiltrat lymphocytaire (TILS) de ces CSTN. Il s’agit probablement du sous-groupe de cancers du sein le plus immunogène avec des taux de TILS pré-CNA parmi les plus élevés avec les tumeurs HER2-positives. Cet infiltrat lymphocytaire est d'ailleurs très corrélé aux gènes de notre module immunitaire pronostique dans les CSTN. La valeur prédictive et pronostique des TILS du stroma tumoral est différente selon le sous-type moléculaire de cancer du sein, suggérant une immunité complètement différente de ces tumeurs. Le taux de TILS varie également différentiellement au sein de chaque sous-groupe sous l'influence de la CNA, témoignant d'une interaction complexe entre les TILS et les traitements. Nous montrons que la cinétique des TILS sous l'effet de la CNA est un indicateur pertinent de réponse à la CNA avec une réponse d'autant plus importante qu'une décroissance du taux de TILS sera importante. Les tumeurs les plus immunogènes avec une activité immunitaire importante sont donc les tumeurs triple-négatives les plus favorables. L'un des challenge des années à venir sera donc d'identifier le plus tôt possible les CSTN les moins immunogènes susceptibles de bénéficier au mieux des immunothérapies seules ou combinées au traitement chimiothérapique afin d'activer ou de rétablir précocement une immunité déficiente. Sous une même dénomination de TILS se trouve très certainement des populations phénotypiques de lymphocytes différentes. En effet, après CNA, leur valeur pronostique est opposée entre les CSTN et les tumeurs HER2-positives: des taux élevés de TILS sont associés à un pronostic défavorable dans les tumeurs HER2-positives alors qu’ils ont une tendance à être associés à des CSTN de meilleur pronostic. Les interactions sont complexes entre les agents cytotoxiques et la tumeur et/ou son microenvironnement. L'analyse du résidu tumoral mammaire ou ganglionnaire représente un matériel sous-exploité qui pourrait permettre de mieux comprendre les mécanismes de sensibilité ou de résistance aux traitements. Au delà de la pierre angulaire que constitue l'immunité pour ces tumeurs, nos travaux identifient certains CSTN pour lesquels l'environnement hormonal, au travers de l'indice de masse corporel ou du statut ménopausique, pourrait jouer un rôle. Ainsi l'exploration du métabolome, des particularités immunitaires chez les patientes en surpoids/obèses ou l'analyse de la voie androgène-récepteur (et ses connexions avec les voies oestrogène et progestérone-récepteur) des CSTN doit aussi être explorée de manière détaillée. Ceci ouvre des perspectives de traitement possibles pour certaines patientesTriple negative breast cancer (TNBC) is the most heterogeneous and pejorative subtype of breast cancer. The cornerstone of the treatment of such tumors is based on systemic chemotherapy, more and more frequently administered before surgery, since no targeted therapy has been validated to date. Obtaining a pathological complete response (PCR) is a major favorable prognostic marker as well as an in vivo test of anti-tumor drug susceptibility. The objective of our thesis work was therefore to provide elements of understanding of this heterogeneity through the clinical, biological and molecular dissection of these tumors.We analyzed gene expression profiles of TNBCs and identified 6 distinct molecular subtypes with different biologies and prognoses. This classification used an original methodology based on both classical bioinformatic tools and biological networks. The enrichment of immunity genes from the stromal compartment of the tumor represents a major determinant of the prognosis of these tumors: a strong expression of the immunity genes is associated with a significantly more favorable prognosis.Our main contribution is based on a better understanding of immunity and tumor infiltrated lymphocytes (TILS) of these TNBCs. It is probably the most immunogenic subgroup of breast cancers with the highest TILs levels pre-NAC with HER2-positive tumors. TILS levels are also highly correlated with genes of our immune prognosis module. The predictive and prognostic value of stromal TILS is different according to the molecular subtype of breast cancer, suggesting a completely different immunity of these tumors. The rate of TILS also varies differentially within each subgroup under the influence of the NAC, indicating a complex interaction between TILS and treatments. We show that the kinetics of TILS levels with NAC is a relevant indicator of response to NAC with a response that is all the more important that a decrease in the TILS rate will be important. The most immunogenic tumors with an important immune activity are therefore the most favorable triple-negative tumors. One of the challenges of the coming years will therefore be to identify, as soon as possible, the least immunogenic TNBC that can best benefit from immunotherapies alone or in combination with chemotherapeutic treatment in order to activate or restore early a deficient immunity.Under the same denomination of TILS there are probably different phenotypic populations of lymphocytes. Indeed, after CNA, their prognostic value is opposite between the TNBC and the HER2-positive tumors: high levels of TILS are associated with an unfavorable prognosis in HER2-positive tumors whereas they have a tendency to be associated with a better prognosis for TNBC tumors. The interactions are complex between cytotoxic agents and the tumor and / or its microenvironment. The analysis of the breast or axillary lymph node residual disease represents an underutilized material that could lead to a better understanding of the mechanisms of sensitivity or resistance to treatment.Beyond the key role immunity for these tumors, our work identifies some TNBCs for which the hormonal environment, through the body mass index or the menopausal status, could play a role. Thus, the exploration of the metabolome, immune features in overweight / obese patients or the analysis of the androgen-receptor pathway (and its connections with the estrogen and progesterone-receptor pathways) of the TNBC must also be explored. This opens up possible treatment perspectives for some patients
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Jacqueline, Camille. „Communautés d’agents infectieux et incidence des cancers : le rôle de l’écologie du système immunitaire“. Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT066.
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Le cancer est un problème majeur en santé humaine représentant l’une des principales causes de décès dans le monde. Depuis le début du 20ème siècle, le parasitisme a émergé comme un facteur déterminant pour expliquer la vulnérabilité face au cancer, avec un nombre croissant d’agents infectieux reconnus comme oncogènes. En parallèle, les virus oncolytiques ont attiré une attention considérable pour leur intérêt thérapeutique. Cependant, le rôle des autres agents infectieux dans le développement du cancer est resté largement inexploré même s’ils sont l’un comme l’autre soumis aux pressions du système immunitaire. Ainsi, l’objectif de cette thèse a été d’évaluer l’implication des communautés d’agents infectieux, non-oncogènes et non-oncolytiques, dans le processus cancéreux. Grâce à un modèle de tumeur chez la drosophile, nous avons pu démontrer que les infections sont capables de modifier l’équilibre du système immunitaire avec des conséquences significatives sur l’accumulation des cellules cancéreuses. Considérant que les humains sont exposés à de nombreuses infections de manière successive ou concomitante au cours de leur vie, nous avons pu montrer que l’histoire personnelle d’infection module le risque cancéreux via les perturbations continues qu’elle inflige au système immunitaire. Enfin, les résultats obtenus par l’analyse de jeux de données à l’échelle mondiale suggèrent que les agents infectieux sont également capables d’altérer l’incidence des cancers d’origine infectieuse en interagissant avec les agents oncogènes au sein des communautés infectieuses. À la lumière des interactions réciproques entre infections et cancer, il semble indispensable d’évaluer la pertinence des nouvelles approches de lutte contre le cancer dans le contexte des maladies transmissiblesCancer represents a huge public health issue as a major cause of death worldwide. Since the beginning of the 20th century, parasitism has emerged as a fundamental mechanism for cancer causation with a growing number of infectious agents recognized as oncogenic. Meanwhile, oncolytic viruses have also attracted considerable interest as possible agents of tumor control. Nevertheless, the role of other infectious agents in cancer development has been largely neglected even if they are both exposed to immune system pressures. Thus, the main objective of this PhD was to evaluate the implication of infectious communities, formed by non-oncogenic and non-oncolytic agents, in carcinogenesis. Using a drosophila tumor model, we demonstrated that infections are able to jeopardize immune system responses in a way that significantly impacts cancer cell accumulation. Considering that humans are exposed to a myriad of infectious agents both successively and concomitantly throughout their lives, we have shown that personal history of infection can alter cancer risk through continuous perturbations of the immune system. Finally, results obtained from the analysis of worldwide databases have suggested that infections are able to mold population-level incidences of cancers with an infectious origin, through their interactions with oncogenic agents in infectious communities. In light of the reciprocal interactions between cancer and infections, new anit-cancer therapeutic strategies should be evaluated in the context of co-occurring transmissible diseases
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Yi, Xin. „RNASE L MANIPULATES MACROPHAGES IN INNATE IMMUNITY AND TUMOR GROWTH“. Cleveland State University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=csu1342151674.
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Kerr, J. P. „Cytotoxic T cell costimulation : biology and potential for generating long-lasting immunity“. Thesis, University of Southampton, 2011. https://eprints.soton.ac.uk/375471/.
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Wu, Salene M. „Relationship of General and Health-related Anxiety and Worry to Markers of Inflammation in Women with Advanced Cancer“. The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1356624916.
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