Дисертації з теми "Réponse aux thérapies"
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Girard, Nicolas. "Réponse des chondrosarcomes aux traitements conventionnels et recherche de thérapies innovantes." Caen, 2015. http://www.theses.fr/2015CAEN2070.
Повний текст джерелаChondrosarcomas (CHS) are malignant bone mesenchymal tumors and known to be radio- and chemo-resistant. In this context, the aim of this study was to determine their sensitivity to conventional treatments (X-ray and cisplatin), to better characterize their resistance mechanisms and to identify new therapeutics targets (epigenetic therapy targeting the methyltransferase EZH2 and hadrontherapy by carbon ions). First, we showed that CHS had different sensitivities to X-rays and cisplatin. Moreover, X-rays induced apoptosis or senescence of sensitive cells whereas cisplatin induced only apoptosis. Resistance mechanisms are different and are strongly linked to CHS type. Furthermore, we showed for the first time that CHS were more sensitive in vitro to carbon ions than X-rays. Second, we investigated the efficiency of epigenetic therapy using an EZH2 inhibitor. We showed that the inhibitor reduces chondrosarcomas growth, both in vitro and in vivo. However, its molecular mechanisms remains unclear even if it is independent of EZH2. This work highlights the heterogeneity and the variety of chondrosarcomas responses to conventional treatments. Therefore, it is of importance to use chondrosarcomas with different grades and origins. Moreover, we confirm the interest of the hadrontherapy by carbon ions to treat CHS
Perkins, Géraldine. "Marqueurs moléculaires prédictifs de réponse aux thérapies ciblées dans les cancers digestifs." Phd thesis, Université René Descartes - Paris V, 2012. http://tel.archives-ouvertes.fr/tel-00829655.
Повний текст джерелаHarlé, Alexandre. "Marqueurs de réponse aux thérapies ciblées et personnalisation thérapeutique dans les cancers colorectaux métastatiques." Thesis, Université de Lorraine, 2014. http://www.theses.fr/2014LORR0267/document.
Повний текст джерелаColorectal cancer is the third most common cancer worldwide with more than one million patients diagnosed each year, among 50% will develop metastatic disease. Recent efforts to improve the treatment of metastatic colorectal cancer (mCRC) has led to the development of monoclonal antibodies such as cetuximab and panitumumab, that inhibit the activation of the Epidermal Growth Factor Receptor (EGFR) and its downstream pathways (namely RAS/RAF/MAPK and PI3K/AKT/mTOR) that promote cell growth, proliferation, inhibition of apoptosis, invasion and metastasis. However, from studies including “RAS wild-type” i.e. KRAS and NRAS wild-type tumors, the response rates to cetuximab or panitumumab therapy ranged from only 40 to 60% which results in a large fraction of patients without any known causes for treatment failure. The presence of alterations in other genes such as PIK3CA or BRAF in the EGFR-dependent signaling pathways is responsible for some of the non-responding cases. Moreover, overexpression or alterations of proteins such as PTEN, PI3K, AKT, involved in the RAS/RAF/MAPK or PI3K/AKT/mTOR signaling pathways can have a significant impact on cell proliferation or apoptosis. Absence or overexpression of proteins under their active phosphorylated forms may be of interest to predict response to anti-EGFR in RAS wild-type patients. In this work, we first developed assays to assess RAS and PIK3CA mutations in formalin fixed paraffin embedded colorectal tumors, then we validated these assays according to ISO 15189 and we finally studied expression of downstream signalling phosphoproteins and KRAS, NRAS, BRAF and PIK3CA status in 100 frozen samples of patients with mCRC and treated with anti-EGFR. Among the 100 tumor samples, 60 were RAS wild-type. Among the RAS wild-type patients, 45.0% achieved a complete or partial response, and 55.0% had a stable disease or progression (p<0.001) when treated with anti-EGFR. Patients with a RAS mutation had significant lower progression-free survival (PFS) (HR=3.04[1.91; 4.83];p<0.001) and overall survival (OS) (HR=2.49[1.56; 3.97];p<0.001). PFS and OS were significantly higher in RAS wild-type patients. Expression of pAKT, pERK1/2 and pMEK1 was significantly lower in RAS wild-type patients than in RAS mutated patients (p=0.0246; p=0.004; p=0.0110 respectively) and no significant difference was observed between RAS wild-type and RAS mutated tumors in the expression of pEGFR, pGSK3, pIGFR, pP70S6K and pP90SRK. In RAS wild-type patients, response rate was significantly higher for tumors that overexpressed pEGFR and pAKT above the calculated threshold (p=0.0258 and p=0.0277 respectively). No significant relation was found between response rate and the level of expression of the other phosphoproteins. Our study shows that combining the analysis of the expression of EGFR downstream signalling phosphoproteins, RAS, BRAF or PIK3CA status could be of interest to predict the response to anti-EGFR therapies in patients with mCRC
Abou, faycal Chérine. "Le sVEGFR1 : quel rôle dans la réponse aux thérapies antiangiogéniques dans les carcinomes pulmonaires squameux ?" Thesis, Université Grenoble Alpes (ComUE), 2016. http://www.theses.fr/2016GREAV022/document.
Повний текст джерелаVascular endothelial growth factors (VEGFs) and their receptors are regulators of physiological and pathological angiogenesis. In patients with squamous cell lung carcinoma (SCC), clinical trials evaluating anti-angiogenic therapies (AAG) have failed to identify strong benefits. Rather, these patients are at higher risk of bleeding complications when exposed to Bevacizumab (BVZ), a humanized monoclonal anti-VEGF-A antibody. The soluble VEGF receptor-1, namely sVEGFR1, is a truncated version of the cell membrane-spanning VEGFR1 that only retains the first six N-terminal Ig-like extracellular motifs of VEGFR1 owing to alternative splicing of its pre-mRNA. As a consequence, sVEGFR1 is mainly viewed as an anti-angiogenic factor that counteracts VEGF-A functions on endothelial cells. Moreover, high levels of sVEGFR1 were correlated with bad prognosis and bad response to therapies in many cancer types. Using various SCC cell lines, we showed that Bevacizumab as well as VEGFR-Tyrosine Kinase Inhibitors (Semaxanib, KI8751) increase the intra- and extra-cellular levels of sVEGFR1. We confirmed this up-regulation in NCTU-induced SCC murine tumorgrafts models treated with VEGFR-TKI (sunitinib) or anti-VEGFR2 (DC101). Of note, this effect was never observed in the lung adenocarcinoma histological sub-type (ADC), using either cell lines or a mouse model treated in the same conditions. At the molecular level, we identified the VEGF165 and SOX2 proteins as crucial upstream regulators of sVEGFR1 in response to AAG. Moreover, we unraveled an original and SOX2 proteins as crucial upstream regulators of sVEGFR1 in response to AAG. Moreover, we unraveled an original ines or a mouse model treato discriminate between AAG-sensitive or -resistant SCC cells. Finally, in a series of 77 Non Small Cell Lung Carcinoma, we provided the first description of a differential pattern of sVEGFR1 expression with 11% and 44% of SCC exhibiting no or high expression respectively, high levels of sVEGFR1 being correlated with advanced pTNM stages. As a whole, our results provide the first evidence that AAG therapies upregulate sVEGFR1 expression in SCC cells. In addition, our data highlight an unexpected pro-tumoral function of sVEGFR1 through the activation of a beta 1 integrin-dependent VEGFR autocrine loop. These results might help to understand why SCC are less responsive to anti-angiogenic drugs than ADC and to identify SCC patients eligible to these therapies
Lion, Maëva. "Biomarqueurs prédictifs de la réponse aux traitements par thérapies ciblées dans le cancer du sein." Thesis, Université de Lorraine, 2015. http://www.theses.fr/2015LORR0287.
Повний текст джерелаBreast cancer is the most frequently diagnosed cancer in women and is a real public health problem.Advances in molecular biology have allowed the characterization of the major signaling pathways and revealed their major implication in carcinogenesis processes. Molecular targets have been identified and have enabled the development of targeted therapies, such as monoclonal antibodies, or kinase inhibitors. Despite these considerable advances that have improved the care of patients, emerging of resistance to treatments has been observed. The aim of this work was to identify new tumor biomarkers and determine their clinical significance, their theranostic interest and their impact on the response to targeted therapies. Initially, we studied the activating mutations of the PIK3CA gene. These mutations are found in 25% of breast cancers and are involved in resistance to trastuzumab, antiestrogens and mTOR inhibitors. We analyzed 149 invasive breast tumor samples for PIK3CA gene mutations by PCR-HRM (High Resolution Melting) and 118 by PCR-ARMS (Amplification Refractory Mutation System). The results achieved with the 2 techniques were consistent (k = 0.845; p <0.001) and a relationship between PIK3CA mutations and grade SBR was highlighted with a lower occurrence of mutations in SBR grade III tumors (p=0.025 in HRM and p=0.009 in ARMS). Secondly, we investigated the functional alteration of PI3K/AKT/mTOR, RAS/RAF/MAPKinases and P38MAPKinase signaling pathways. We have analyzed the expression level of phosphoproteins p-AKT, p-GSK3ß, p-S6 kinase, p-MEK1, p-ERK1 / 2, p-P90RSK, p-IGF1R and p-p38MAPK by multiplex immunoanalysis. This part includes 3 studies. The first study was a retrospective study of 45 frozen samples of invasive breast tumors in which we observed that the level of expression of P38 and p-P38 was higher in the ER + tumors. The second study was a prospective study to identify biomarkers of response to trastuzumab-everolimus association in patients with early breast cancer treated preoperatively. This study showed a statistically significant increase of the expression level of p-MEK1 (p = 0.012), p-ERK1/2 (p = 0.003) and p-p38MAPK (p<0.001) in arm treated by trastuzumab associated with everolimus. It could be explained by the repression of a negative feedback loop involving S6K, PI3K and RAS by everolimus, leading to the activation of RAS/RAF/MAPKinases signaling pathway. In the control arm investigating trastuzumab alone, no significant variations of the level of expression of phosphoproteins was demonstrated, raising the hypothesis of the implementation of a predominant immunological mechanism of action for Trastuzumab. The third study that compared effect of trastuzumab in vitro and in clinical setting confirms that trastuzumab has different modes of action when evaluated in cells and in clinical conditions. As a whole, this work showed that determining the mutation status of PIK3CA and the expression level of phosphoproteins could be useful to refine the molecular characterization of breast cancers and optimize the criteria used to personalize the prescription of targeted therapies
Gremeaux-Funck-Brentano, Elisa. "Marqueurs prédictifs de réponse aux inhibiteurs de BRAF dans le mélanome cutané métastatique." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS216/document.
Повний текст джерелаTargeted therapies have improved survival in patients with metastatic cutaneous melanoma, but some patients escape treatment. Response to treatment involves parameters dependent of the patient, the tumor biology, and the occurrence of resistance mechanisms extensively investigated. The aim of this work is to study two measurable markers in clinical practice in patient monitoring, for their predictive potential of response to BRAF inhibitors monotherapy; the first one is biological and the other one is pharmacological: mutant allele burden (MAB), defined by the ratio mutant/total, of BRAF and NRAS oncogenes, and plasma vemurafenib concentration (PVC).We report for the first time the prevalence and the mechanisms of BRAF and NRAS oncogenic allelic imbalance, defined by a high (>60%) or a low (≤30%) MAB, as opposed to a balanced “heterozygous” MAB (30 to 60%). In vitro experiments and in vivo data support the hypothesis that a BRAFV600E MAB >60% may be associated with a better response to BRAF inhibitors. NRAS MAB does not seem to be a baseline prognostic marker, but its predictive value of response to MEK inhibitors will be interesting to investigate.We demonstrated for the first time the impact of CPV assay during the monitoring of patients treated with monotherapy. A low CPV would be predictive of progression; thus, CPV appears to be an original predictive marker of response, for which the threshold value and the involved pharmacogenetic mechanisms remain to be determined
Billy, Frédérique. "Modélisation mathématique multi-échelle de l'angiogenèse tumorale : analyse de la réponse tumorale aux traitements anti-angiogéniques." Phd thesis, Université Claude Bernard - Lyon I, 2009. http://tel.archives-ouvertes.fr/tel-00631513.
Повний текст джерелаChastel, Carine. "Développement de thérapies anti-angiogéniques combinées à l'irradiation : étude de la réponse de promoteurs aux radiations ionisantes." Université Joseph Fourier (Grenoble), 2003. http://www.theses.fr/2003GRE10071.
Повний текст джерелаFrenel, Jean-Sébastien. "Evaluation de l'ADN circulant tumoral (ADNct) comme biomarqueur de réponse aux thérapies ciblées développées en phase précoce en oncologie." Thesis, Nantes, 2018. http://www.theses.fr/2018NANT1013/document.
Повний текст джерелаCirculating cell free DNA (ccDNA) deriving from tumor can be isolated in plasma of cancer patients. This circulating tumor DNA (ctDNA) shared the same genetics and epigenetics characteristics with the tumor and represents virtually a liquid biopsy. We evaluated whether targeted next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) could be used for patient selection and as a tumor clone response biomarker in 39 patients with advanced cancers participating in early-phase clinical trials of targeted drugs. Overall, 159 plasma samples were sequenced with a mean sequencing coverage achieved of 1,685X across experiments. At trial initiation (C1D1), 23 of 39 (59%) patients had at least one mutation identified in cfDNA. Out of the 44 mutations identified at C1D1, TP53, PIK3CA and KRAS were the top three mutated genes identified, with 18 (41%), nine (20%), eight (18%) different mutations, respectively. In the second part of this work, we performed sequential NGS of ctDNA for the 23 patients with cfDNA mutation identified at C1D1. The monitoring of mutation allele frequency (AF) in consecutive plasma samples during treatment with targeted drugs demonstrated potential treatment associated clonal responses. Longitudinal monitoring of cfDNA samples with multiple mutations indicated the presence of separate clones behaving discordantly. Molecular changes at cfDNA mutation level were associated with time to disease progression. Targeted NGS of ctDNA has potential clinical utility to monitor the delivery of targeted therapies and future directions are discussed
Chrétien, Anne-Sophie. "Fonctionnalité de la signalisation en aval des récepteurs HER : implication dans la réponse cellulaire et tumorale aux thérapies ciblées." Thesis, Nancy 1, 2011. http://www.theses.fr/2011NAN10050/document.
Повний текст джерелаTargeted therapies, monoclonal antibodies and tyrosine kinase inhibitors, directed against the Human Epidermal Growth Factor Receptors (HER) family, represent a major advance in oncology. Their efficacy depends on their ability to inhibit oncogenic signalling, including the RAS/RAF/MAPK and PI3K/AKT signalling pathways. Regardless of the expression of the molecular target, the efficacy of targeted therapies is independent on the genetic abnormalities of the tissue which are able to disrupt tumour cell signalling, and the research of these abnormalities is now included in the prescription criteria. The aim of this work was to evaluate the usefulness of assessing HER downstream signalling functionality using multiplex analysis of the phosphorylated forms of key intracellular kinase signalling. Proof of concept was first introduced with genetically modified cell lines models, showing the consequences of tumour genetic abnormalities on RAS/RAF/MAPK and PI3K/AKT signalling pathways and on response to cetuximab. In the second part of this work, after validation of the techniques used in clinical situation, we demonstrated the relevance of system biology approach, combining molecular biology and functional analysis with principal component analysis. Our results obtained in a retrospective clinical study in metastatic colorectal cancer, suggests that the use of data from the evaluation of HER downstream signalling pathways functionality could eventually find applications as predictive markers of clinical response to anti-HER targeted therapies
Kammerer-Jacquet, Solène-Florence. "Carcinome à cellules claires du rein : phénotype métastatique et résistance aux thérapies ciblées." Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B038.
Повний текст джерелаClear cell renal cell carcinoma (ccRCC) is the most common kidney cancer. It is characterized by frequent inactivation of the tumor suppressor gene VHL found in 70% of tumors leading to the transcription of HIF transcription factor target genes such as VEGF. This is an aggressive tumor with 50% of metastatic patients. Sunitinib, an inhibitor of receptor tyrosine kinase antiangiogenic, is currently the most used in 1st line despite 30% of patients who progress quickly. The advent of a new anti-angiogenic targeting MET (cabozantinib) and immunomodulators (anti-PD-1 antibody, nivolumab) makes crucial discovery of predictors of response to treatment. In the first part, we studied a retrospective study of 98 consecutive ccRCC. We assessed complete VHL status and correlated it with the expression of PD-L1. Moreover, while the prognosis is different between ccRCC synchronous metastatic and metachronous, their phenotype have never been compared. In this purpose, we performed an analysis of the main pathological prognostic factors, immunohistochemical markers (CAIX, VEGF, PAR3, PD-1 and PD-L1) and molecular (VHL status: deletion, mutation and promoter methylation) correlated with specific survival. We demonstrated that non-inactivated VHL tumors (niVHL) were associated with the presence of synchronous metastases, sarcomatoid component, a dense lymphocytic infiltrate, an overexpression of VEGF, an expression of PD-L1 and a poor prognosis. We also compared the phenotypes of metachronous and synchronous metastatic ccRCC. The first ones were associated with sarcomatoid component, cytoplasmic expression of PAR-3 overexpression VEGFA and niVHL status and a poor prognosis even from the diagnosis of metastases. In the second part, we studied a retrospective study of 90 consecutive metastatic ccRCC treated with first line sunitinib to identify predictors of response or resistance. We used the same techniques as above plus the MET status (mutation in Next-Generation sequencing and expression by IHC). Patients were classified as primary-refractory, intermediate and long-term responders depending on the duration of their response as assessed by radiological criteria (RECIST). We also characterized the genetic profile of 73 ccRCC of this series by CGH array for which we had frozen tumor. Primary refractory patients often had poor prognosis (Heng criteria), liver metastases, infiltration of the hilar fat. Cytogenetically, their tumors had many more genetic alterations, both gains as losses. These recurrent alterations were gains of 5p, 7p, 8q22.1-qter and loss of 6q21-q25.3 region. The multivariate Cox model highlighted four independent factors: the score of Heng, liver metastases, infiltration of the hilar fat and gain of 8q which integrated into a prognostic nomogram had a c-index of 0.74 for survival progression-free survival and 0.77 for overall survival. In conclusion, our study identified a subtype of ccRCC with a poor prognosis with niVHL status that should be explored at the genomic level. Furthermore, we showed a phenotype difference between ccRCC synchronous and metachronous metastatic patients whereas their care is currently the same. Finally we have identified a prognostic nomogram in metastatic ccRCC treated with sunitinib in the first line. This nomogram if confirmed by a larger prospective study could have a significant clinical impact in the selection of patients most likely to benefit from anti-angiogenic therapy
Boudria, Asma. "Les variants d'épissage du VEGF-A : leur rôle dans la progression et la réponse aux thérapies anti-angiogéniques des carcinomes pulmonaires." Thesis, Grenoble, 2014. http://www.theses.fr/2014GRENV010/document.
Повний текст джерелаVEGF-A is one of the most important factors during tumor neoangiogenesis. This role has made it a prime target for the development of therapies. Thus, various drugs targeting VEGF-A (Bevacizumab, Avastin®) or its signaling pathways (VEGFR inhibitors) are currently used in clinical practice, especially in lung adenocarcinomas treatment. However, despite promising initial results, many patients are refractory or escape these therapies, and sometimes, even develop more aggressive tumors. To date, there is no means to identify patients who are likely to respond these treatments. Recently, new splicing variants of VEGF-A resulting from an alternative splicing at the last exon, were identified and called VEGFxxxb. Unlike VEGFxxx, these variants are antiangiogenic. If paracrine effects of VEGF-A isoforms on endothelial cells have been well characterized, few studies have examined their autocrine effects on tumor cells expressing VEGFR1 and VEGFR2. In this context, the main aim of our study was to determine the expression status and biological functions of VEGF165b in primary tumors and derived cell models of non small cell lung carcinoma (NSCLC). Our results identify variable expression profiles of VEGF165b in NSCLC patients, and show that high levels of intratumoral VEGF165b are associated with lymph node metastases. Furthermore, our results identify an autocrine loop through which the VEGFR1/VEGFR2 activation by VEGF165b leads to the appearance a more invasive phenotype on tumor cells. Finally, our results show that treatment of tumor cells by Bevacizumab (BVZ) but also platinum salts, with which it is associated clinics, increases VEGF165b expression and autocrine signaling, which leads to appearance of tumor cells that are more aggressive and resistant to cisplatin-induced apoptosis. These results are the first evidence of the VEGF165b ability to signalize on tumor cells. In a second stage of our work, we investigated the potential role of β1 and β3 integrins in maintaining VEGF165b signaling in NSCLC cells. We show that VEGF165b activates beta1 integrin. This activation leads to a rearrangement of the actin cytoskeleton in stress fibers, which may promote tumor cell migration. Interestingly, BVZ is able to induce this same phenotype by a mechanism requiring the expression of VEGF165b , beta1 integrin and beta3 integrin. The formation of these stress fibers is associated with the activation of downstream signaling pathways involving proteins phosphorylation of FAK and cofilin. In addition, we highlight the existence of neuropilin-2/β1 integrin complexes in NSCLC cells, which are likely to participate in these pathways activation. Thus, VEGF165b and especially BVZ appear able to signal through beata1 and beta3 integrins NSCLC cells, suggesting a role of these integrins in tumor cells response to antiangiogenic therapies. In conclusion, our results are the first evidence of a role of VEGF165b in NSCLC progression and response to antiangiogenic therapies and chemotherapies; they suggest that VEGF165b could be a marker of response to BVZ in NSCLC
Loyher, Pierre-Louis. "Rôle du récepteur de chimiokines CCR2 dans la dynamique des lymphocytes T régulateurs et monocytes/macrophages en réponse aux thérapies antitumorales." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066010/document.
Повний текст джерелаMalignant and stromal cells are strong producer of the chemokine CCL2 in most human cancers. The chemokine axis CCR2/CCL2 is thus a key marker of cancer development, but is also associated with relapse following therapy. Tumour associated macrophages (TAM) and regulatory T cells (Treg) display robust immunosuppressive capacities and contribute to tumour growth. My thesis work focused on the function of the expression of the chemokine receptor CCR2 by these cell types in the context of anticancer therapies. We have shown that CCR2 controls the migration of Treg in tumoral context, in both human and mice, and that the expression of this receptor by Treg could serve as a biomarker of the response to chemotherapy. Our study indicate a novel function of CCR2, defining at the same time a new Treg subset implicated in the regulation of antitumor immunity.We have also demonstrated that pulmonary metastases are composed of both tissue resident and recruited macrophages. The presence of resident macrophages within tumours could contribute to the heterogeneity of the microenvironment of different tumour types. CCR2 is largely implicated in the relapse phase following chemotherapy, indicating a limited role for resident macrophages in this phenomenon. Meanwhile, we have demonstrated that VEGF plays a direct role in TAM survival. The combination of chemotherapy with an anti-VEGF antibody targets both resident and recruited TAM, thereby enhancing the efficacy of chemotherapy. Finally, we have shown that the CCR2/CCL2 axis is implicated in the response to radiotherapy by enhancing the recruitment of both Treg and TAM. This work provides evidences for a central role of the CCR2/CCL2 axis in mediating Treg and TAM co-localization in response to anticancer therapy, this axis could also contribute to establishment of immunosuppressive networks in tumours. Our results provide a better understanding of the immune mechanism implicated in resistance to anticancer therapies
Loyher, Pierre-Louis. "Rôle du récepteur de chimiokines CCR2 dans la dynamique des lymphocytes T régulateurs et monocytes/macrophages en réponse aux thérapies antitumorales." Electronic Thesis or Diss., Paris 6, 2017. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2017PA066010.pdf.
Повний текст джерелаMalignant and stromal cells are strong producer of the chemokine CCL2 in most human cancers. The chemokine axis CCR2/CCL2 is thus a key marker of cancer development, but is also associated with relapse following therapy. Tumour associated macrophages (TAM) and regulatory T cells (Treg) display robust immunosuppressive capacities and contribute to tumour growth. My thesis work focused on the function of the expression of the chemokine receptor CCR2 by these cell types in the context of anticancer therapies. We have shown that CCR2 controls the migration of Treg in tumoral context, in both human and mice, and that the expression of this receptor by Treg could serve as a biomarker of the response to chemotherapy. Our study indicate a novel function of CCR2, defining at the same time a new Treg subset implicated in the regulation of antitumor immunity.We have also demonstrated that pulmonary metastases are composed of both tissue resident and recruited macrophages. The presence of resident macrophages within tumours could contribute to the heterogeneity of the microenvironment of different tumour types. CCR2 is largely implicated in the relapse phase following chemotherapy, indicating a limited role for resident macrophages in this phenomenon. Meanwhile, we have demonstrated that VEGF plays a direct role in TAM survival. The combination of chemotherapy with an anti-VEGF antibody targets both resident and recruited TAM, thereby enhancing the efficacy of chemotherapy. Finally, we have shown that the CCR2/CCL2 axis is implicated in the response to radiotherapy by enhancing the recruitment of both Treg and TAM. This work provides evidences for a central role of the CCR2/CCL2 axis in mediating Treg and TAM co-localization in response to anticancer therapy, this axis could also contribute to establishment of immunosuppressive networks in tumours. Our results provide a better understanding of the immune mechanism implicated in resistance to anticancer therapies
Long-Mira, Élodie. "Identification de biomarqueurs tissulaires et sanguins impliqués dans la progression, la réponse et la résistance aux thérapies ciblées des mélanomes cutanés." Thesis, Université Côte d'Azur (ComUE), 2016. http://www.theses.fr/2016AZUR4129.
Повний текст джерелаBackground: Knowledge of the BRAFV600E status is mandatory in metastatic melanoma patients (MMP). Molecular biology is currently the gold standard method for status assessment. The aim of this work was to assess and compare several methods of molecular biology and immunohistochemistry (IHC) in tissue and blood (cell-free circulating tumor DNA, circulating tumor cell (CTC)) to identify predictive biomarkers of response or resistance to targeted treatment. Results: We showed that BRAFV600 IHC could be a substitute for molecular biology in the initial assessment of the BRAFV600E status in MPP. We also found that the presence of circulating tumor cell detetcted by a cytomorphological approach ISET (Isolation by Size of Epithelial Tumor Cell – Rarecells Diagnostics, Paris, France) in MMP is an independent predictor of shorter survival. Then, in a monocentric study conducted at the University of Nice Hospital, we evaluated a novel and fully automated CE-IVD PCR-based system (IdyllaTM, Biocartis, Mechelen, Belgium) for plasmatic BRAF and NRAS mutation detection. We showed that this technology is highly sensitive and specific and provide promising potential to assess tumor progression, identify targets for therapy, and evaluate clinical response to treatment. In conclusion, identification of tissue and blood biomarkers with these technologies allow a quick turnaround-time to BRAF/NRAS diagnosis and improve monitoring of treatment response and development of resistance in metastatic melanoma patients
Long-Mira, Élodie. "Identification de biomarqueurs tissulaires et sanguins impliqués dans la progression, la réponse et la résistance aux thérapies ciblées des mélanomes cutanés." Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2016. http://www.theses.fr/2016AZUR4129.
Повний текст джерелаBackground: Knowledge of the BRAFV600E status is mandatory in metastatic melanoma patients (MMP). Molecular biology is currently the gold standard method for status assessment. The aim of this work was to assess and compare several methods of molecular biology and immunohistochemistry (IHC) in tissue and blood (cell-free circulating tumor DNA, circulating tumor cell (CTC)) to identify predictive biomarkers of response or resistance to targeted treatment. Results: We showed that BRAFV600 IHC could be a substitute for molecular biology in the initial assessment of the BRAFV600E status in MPP. We also found that the presence of circulating tumor cell detetcted by a cytomorphological approach ISET (Isolation by Size of Epithelial Tumor Cell – Rarecells Diagnostics, Paris, France) in MMP is an independent predictor of shorter survival. Then, in a monocentric study conducted at the University of Nice Hospital, we evaluated a novel and fully automated CE-IVD PCR-based system (IdyllaTM, Biocartis, Mechelen, Belgium) for plasmatic BRAF and NRAS mutation detection. We showed that this technology is highly sensitive and specific and provide promising potential to assess tumor progression, identify targets for therapy, and evaluate clinical response to treatment. In conclusion, identification of tissue and blood biomarkers with these technologies allow a quick turnaround-time to BRAF/NRAS diagnosis and improve monitoring of treatment response and development of resistance in metastatic melanoma patients
Le, Grand Adélaïde. "Etude comparative de récepteurs aux œstrogènes : Aspects moléculaire et cellulaire de la réponse aux œstrogènes et anti-œstrogènes impliqués dans les causes et thérapies du cancer du sein." Phd thesis, Université de Bretagne Sud, 2009. http://tel.archives-ouvertes.fr/tel-00470517.
Повний текст джерелаLe, Grand Adélaïde. "Étude comparative de récepteurs aux œstrogènes : aspects moléculaire et cellulaire de la réponse aux œstrogènes et anti-œstrogènes impliqués dans les causes et thérapies du cancer du sein." Lorient, 2009. http://www.theses.fr/2009LORIS166.
Повний текст джерелаEstrogens (E2), through estrogen receptors (ERs), control the expression of a number of genes involved in growth, cellular differentiation and reproductive functions. Regulation of these genes is carried out by the ER binding to a DNA sequence: the Estrogen Responsive Element (ERE). ERs play a major role in breast cancer and therefore it’s important to understand the molecular mechanisms which modulate ER activity in vivo. We found that, compared to the consensus ERE, ERs exhibit a lesser affinity for the imperfect ERE (rtvtgERE), cellular activity and E2 sensitivity. An in vitro study on the ERs conformational, thermodynamical and dynamical behaviour has proved that the electrostatic network plays a role in their different functionalities. We researched and compared the impact of the ligands fixation on the cellular activity of two ER: hER and rtERS. The transcriptional mechanism created in yeast allowed us to show that hER is a transcriptional activator which is more potent and more sensitive to E2 than rtERS. We observed that the presence of the ligand induces ER localization within foci. Time curses of the ER transcriptional activation and sub-cellular localization in the presence of ligands lead us to distinguish these two aspects. We suggest that a high phosphorylation level by kinases activated in the presence of ligand increases the ER anionic character tending either to prevent the fixation on the DNA or to increase their dissociation from the DNA. Thus, ERs could be recruited by complexes in the nucleus or cytoplasm and form some foci
Brun, Agnès. "Développement de thérapies pharmacologiques innovantes dans le traitement des dégénérescences rétiniennes héréditaires." Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ076.
Повний текст джерелаRetinitis pigmentosa is the first cause of inherited retinal degeneration affecting 1.5 million persons worldwide. Currently, there is no available treatment for most of these diseases. Based on a previous study, the project aims to develop a treatment for some of them. The tested approach targets a common cellular pathway activated in many of these diseases; the Unfolded Protein Response (UPR), pathway activated in response to a stress due to a protein overload. The treatment decreases this overload. is the treatment is composed of IFB-088, a GADD34/PP1c inhibitor, allowing maintaining the translation inhibition and of valproic acid which increases BiP and the folding capacities of the reticulum. The treatment was tested in two models displaying UPR activation. In these models, the treatment slow-down the short-term retinal degeneration by decreasing cellular stress to maintain visual capacities
Pohorecka, Magdalena. "Rôle de c-Jun dans la réponse aux inhibiteurs de la voie des MAPK dans les mélanomes." Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30373.
Повний текст джерелаIt is clearly recognized that the MAPK pathway is essential for melanomagenesis. The development of new drugs targeting this pathway such as BRAF inhibitors and/or MEK inhibitors has been a major advance in the therapeutic management of melanoma. However, patients still relapse suggesting the emergence of mechanisms of resistance. Many data show that both the expression and activation of the transcription factor c-Jun are induced after treatment of BRAF-mutant cells with MAPK pathway inhibitors (MAPKi). Furthermore, depletion of c-Jun sensitizes cells to these inhibitors triggering apoptosis. We depleted BRAF-mutant melanoma cell lines for c-Jun by siRNA and treated cells with a BRAF inhibitor (PLX4032). Whole genome expression was then analysed by transcriptomic study to determine target genes of c-Jun that could be associated with pharmacological response to MAPKi. This study revealed that SLIT And NTRK Like Family Member 6 (SLITRK6) is a target gene of c-Jun that could be associated with antitumor pharmacological response to MAPKi. Indeed, SLITRK6 mRNA and protein are induced in BRAF-mutant melanoma cell lines after BRAF inhibitor treatment alone or in combination with MEK inhibitor (AZD6244). We also show that the combination of MAPKi with an antibody conjugated with a cytotoxic drug targeting SLITRK6 increases BRAF-mutant melanoma cell death triggering apoptosis in vitro. Finally, our data show that SLITRK6 could be a new pharmacological target for the treatment of BRAF-mutant metastatic melanoma and/or a potential biomarker of resistant cells to MAPKi
Rakotomalala-Andrianasolo, Andria. "Développement et caractérisation de modèles cellulaires pour l'étude du rôle de l'oncohistone H3.3 K27M dans le phénotype agressif et la réponse aux thérapies des gliomes pédiatriques diffus de la ligne médiane." Electronic Thesis or Diss., Université de Lille (2022-....), 2024. http://www.theses.fr/2024ULILS015.
Повний текст джерелаH3K27-altered DMG treatment is one of the most significant challenges in pediatric neuro-oncology,with no improvement in patient survival over the past 50 years. In 2012, it was shown that DMGs harbor a specific histone 3 mutation (oncohistone) called H3.3 K27M with a very high prevalence (70-80% of cases). Although theH3.3 K27M impact on the epigenetic landscape has been well described, studies are needed to understand betterits role in DMG cells’ aggressiveness and response to therapies.To study the H3.3 K27M mutation impact on DMG cell phenotypes precisely, we developed andcharacterized pediatric high-grade glioma isogenic cellular models induced and knock-out for the oncohistone.Using these models, we aimed to decipher the oncohistone impact on DMG cell biology and response to anticancertherapies, including radiation therapy, the only current standard of care for DMGs. Characterization of our H3.3 K27M-induced pediatric supratentorial glioma cell lines reveals that the oncohistone affects the response to ionizing radiations and specific targeted therapies in a cellular context-dependentway. Based on these results, we settled to characterize oncohistone biological impacts in a more relevant cellular context of DMG. In that sense, we established H3.3 K27M knock-out cellular models and characterized them regarding their parental DMG H3.3 K27M mutated cell lines. Through omic (transcriptomic and proteomic)and cell metabolism characterizations of these models, we notably showed the H3.3 K27M mutation impact on DMG cells’ lipid metabolism. In 3D spheroid models, this H3.3 K27M-induced lipid metabolism rewiring appeared conditioned by microenvironment factors still under investigation.On the other hand, a functional pharmacological screen identified H3.3 K27M-driven dependencies tospecific DNA repair pathways. In addition, ongoing radiobiological characterization of our models indicates anH3.3 K27M-associated radiosensitivity correlating with a decrease in DNA repair efficiency following ionizingradiations. Beyond this DNA repair impact, our pharmacological screen also revealed an H3.3 K27M-relatedsensitivity to cardiac glycoside drugs. This result makes sense with our transcriptomic data showing enrichmentin genes involved in cardiomyopathies and ion homeostasis among differentially expressed genes with theoncohistone. In this context, we began unraveling the molecular and biological processes underlying thisH3.3 K27M-driven effect.Finally, we used our isogenic cellular models to show that the H3.3 K27M oncohistone drives lipidmetabolism modifications. These metabolic changes could prime H3K27-altered DMG cells to specific regulatedcell death pathways (e.g., ferroptosis) and affect the response to certain therapies. Moreover, the H3.3 K27Mseems to drive specific sensitivities, notably to radiation therapy and cardiac glycoside drugs. Understanding the underlying molecular mechanisms governing these H3.3 K27M-associated Achille heels could highlight newinsights into the oncohistone role in DMG cells and provide rationales for developing new therapeutic strategies
Pacheco, Nieva Yovana. "Réponse immune cellulaire et thérapie de l'infection par le VIH." Nantes, 2010. https://archive.bu.univ-nantes.fr/pollux/show/show?id=59e1f838-c420-42d8-b4a6-49b9bf87c144.
Повний текст джерелаDuring HIV infection antiretroviral tritherapy efficiently inhibits viral replication and restores CD4 counts in infected patients. Nevertheless treatment failure may occur. In this work, we investigated two different aspects of this problem : Firstly, HIV sequence variability may provoke the emergence of resistant viruses leading to virological failure. The fact that many drug resistance mutations in HIV fall within CTL epitopes suggests that the immune response play a role in inhibiting resistant virus. In order to address this question we analyzed the response against the RT181-189 epitope covering the Lamivudine resistance mutation, M184V in 34 HLA-A2+ HIV+ infected patients. We found that RT181-189 is frequently recognized by ART Naive patients and poorly recognized by patients with virological failure under Lamivudine treatment. Both viral load and viral sequence polymorphism were associated with the presence of a CTL response against RT181-189. Secondly, some patients may undergo immunological failure; the recovery of CD4+ T-cell counts is incomplete despite complete suppression of viral replication. The aim of our study was to compare the effects of IL-2, IL-7, IL-15 and an agonist of IL-15, RLI, on CD4+ and CD8+ lymphocytes from HIV-infected patients, in order to evaluate the therapeutic potential of these molecules on immune reconstitution. Overall our results indicate that the proliferative response of CD4+ T-cells to IL-7 is preserved, even in patients with low CD4+ T-cell counts, and that both IL-15 and RLI can induce homeostatic proliferation of CD4+ effector-memory T-cells. In, RLI did not show greatly increased potency compared to native IL-15
Berment, Perrine. "Modélisation de la réponse au traitement en oncologie : exemples en radiothérapie et en thérapies ciblées." Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0089/document.
Повний текст джерелаWe first present two mathematical models to simulate the evolution and theresponse to treatments of GIST.Then, we study colorectal tumors and radiotherapy response. We present apartial differential equations model to simulate the tumor evolution, the responseto radiotherapy and the PET-scan. We introduce a simplification of thefirst model to develope a calibration technic based on medical images of thetumor. Two applications on clinical cases are presented.To finish, a similar method is adapted to ORL tumors and response to radiotherapyand tested on six clinical cases
Bibeau, Frédéric. "Détermination de facteurs prédictifs de réponse aux anticorps anti-récepteur du facteur de croissance épidermique dans le cancer colorectal métastatique." Clermont-Ferrand 1, 2009. http://www.theses.fr/2009CLF1MM07.
Повний текст джерелаThe goal of this thesis was to assess predictive factors of response to anti-EGFR (Epidermal Growth Factor Receptor) antibodies in metastatic colorectal cancer. We have first shown that immunohistochemical EGFR expression, the initial prerequisite for anti-EGFR antibodies prescription, was similar in primary colon cancer and related metastases. Thus, the lack of discrepancy between primary ans metastases can not explain the absence of correlation between EGFR expression and response, reported in clinical trials. In the second study, we observed that TP53 mutations were predictive of disease control and better progression free survival (PFS), notably in patients harbouring KRAS wild type tumors. TP 53 mutations may caracterize tumors with an activated EGFR pathway, thus particularly sensitive to anti-EGFR antibodies. In this study, KRAS mutations were associated with a lack of response and a shorter PFS, confirming this parameter as a biomarker of resistance to anti-EGFR antibody therapy. In the third study, we analyzed the clinical relevance of polymorphisms of genes encoding for FcγRIIa and RIIIa receptors, expressed by immune effectors, which impact on the affinity of the Fc portion of the therapeutic antibody and thus modulate the ADCC (Antibody-Dependent Cell-mediated Cytoxicity) phenomenon. The KRAS status was also analyzed in combination, showing a negative effect of mutations on response and PFS. Patients with FcγRIIa-131H/H and/or FcγRIIIa-158V/V genotypes, leading to a stronger affinity, had longer PFS than 131R and 158F carriers, including KRAS mutated patients. This work support an important place for pharmacogenomics and pharmacogenetics in the setting of so called "personalized treatments" of mCRC
Torossian, Avédis. "Contrôle de l'expression de Bcl-2 dans les lymphomes anaplasiques à grandes cellules par la protéine HuR en réponse au crizotinib : impact sur l'apoptose et l'autophagie." Thesis, Toulouse 3, 2017. http://www.theses.fr/2017TOU30190/document.
Повний текст джерелаAnaplastic large cell lymphoma (ALCL) are T/-null non-hodgkin lymphoma representing most of childhood T-cell lymphoma (up to 30%). More than 80% of cases bear reciprocal chromosomic translocation responsible for abnormal expression and constitutive activation of X-ALK type (Anaplastic Lymphoma Kinase) chimeric proteins (ALK+ ALCL). A striking characteristic of this lymphoma is that B-Cell Lymphoma-2 (BCL-2) remains undetectable in ALK+ cases compared to ALK- cases. This is all the more surprising as the BCL-2 oncogene, which is firmly established as a prototypic anti-apoptotic factor as well as a key autophagy regulator, has been shown to be overexpressed in a majority of lymphomas. On the other hand, the RNA-binding protein HuR (Human Antigen R) is overexpressed in ALCL (as in most cancers). It has been demonstrated that this protein was involved in the sustainability of the tumoral phenotype, and that its subcellular localization and functions were closely related to its phosphorylation status, which in turn heavily depends on ALK activity in ALK+ ALCL. In the cytoplasm, HuR has the ability to bind adenine and uridine-rich elements (ARE) located on the 3'-UTR of target mRNAs, and both protect them from degradation and increase their translation. From a general point of view, HuR is able to establish an interplay with microRNAs (miRNAs), either blocking them through competition, or actually cooperating with them and thus promote their function of negative regulators of gene expression on common target transcripts. The BCL-2 transcript, which expression seems to be silenced in ALK-expressing ALCL, has been described as a potential target of HuR. During my PhD work, I dedicated myself to understand the molecular mechanism at work in the silencing of BCL-2 expression with a focus on HuR and collaborating miRNA. The data I obtained point at a cooperation between HuR and miR-34a leading to the silencing of the BCL-2 transcript. However, when the ALK tyrosine kinase activity is inhibited, it appears the interaction between the BCL-2 mRNA diminishes, which limitates the miR-34a 's access to this transcript and ultimately results in a re-expression of the BCL-2 oncogene in these lymphoma cells. In the current context of clinical trials for ALK-targeting inhibitors, such as the Crizotinib, this BCL-2 re-expression observed upon ALK inhibition shed light on potential reasons behind some therapeutic failures that have recently been reported. Indeed, during my PhD work, I also studied the consequences of the BCL-2 re-expression observed in Crizotinib-treated cells. The data I obtained in vitro and in vivo show that, by blocking this re-expression using RNA interference, the Crizotinib anti-tumoral efficiency can be greatly potentiated. This potentiation took the form of an increase of apoptotic cell death induction and, interestingly, also affected the autophagic response triggered by the drug, making it switch from a cytoprotective- type, protumoral autophagic flux to an enhanced, deletary-type and tumor suppressive flux, adding to the therapeutic effect of the drug. This work in general provides insights for new therapeutic combinations that could potentially benefit to ALK+ ALCL patients, and illustrates the complex cross-regulations between apoptotic and autophagic pathway
Mourcin, Frédéric. "Etude de la réponse cellulaire et moléculaire des cellules souches et progéniteurs hématopoïetiques aux radiations ionisantes : implication pour la mise en place d'une thérapie cellulaire de l'aplasie médullaire radio-induite." Université Joseph Fourier (Grenoble), 2004. http://www.theses.fr/2004GRE10234.
Повний текст джерелаNew treatments of radio-induced bone marrow aplasia were based on the apoptosis reduction (in vivo or in vitro) of the hematopoietic stem and progenitor cells (HSPC). These approaches were founded on the heterogeneity of irradiation injury, which preserves some HSPC. The autologous cell therapy (ACT) is based on: the collect of residual HSPC and then on a phase of in vitro culture (6 to 7 days) ir the final goal to graft these expanded cells. Our work has consisted to study the fundamental mechanism of radio-induced apoptosis of HSPC before to optimise the ACT. We have used an in vitro model of irradiation of CD34+ cells come from non-human primate. Our results show a complexity of mechanisms that has been implicated in the molecular and cellular response, in case of cell cycle and apoptosis. But Caspases 1 and 6 was seen to play an important role in terms of final effectors. The cultures of irradiated cells show that 1 the negative selection of apoptotic residual HSPC before cell culture did not improve the expansion rate 2) the expansion of 4Gy irradiate CD34+ cells can only be considered with a support stromal has weil has Dexter or Mesenchymal Stem Cells 3) the sequential addition of an inhibitory of haematopoiesis (TNF-a) with a cocktail activation reduce apoptosis and increased expansion of CD34+ irradiated cells. Finally this study 1) suggest different molecular targets for new anti-apoptotic treatments and 2) show the difficulty to used the ACT in the case of an accidental irradiation
Ducellier, Sarah. "Étude de la restauration de la réponse immunitaire antitumorale dans un modèle murin de cancer pulmonaire induit par une molécule multicible inhibitrice de HDAC et du splicéosome." Electronic Thesis or Diss., université Paris-Saclay, 2023. http://www.theses.fr/2023UPASL050.
Повний текст джерелаLung cancer is the second most common cancer worldwide. Immunotherapy has been recently proposed as a treatment. However, several mutations generated by a high rate of epigenetic changes can induce resistance. Histone deacetylases (HDACs) control the acetylation rate of histone and thus modulate gene expression. Inhibition of HDACs by small molecules (HDACi) makes it possible to overcome epigenetic changes and resistance to treatments. Thanks to a collaboration, we were able to study a new multi-target HDACi, able to inhibit the spliceosome machinery, responsible for alternative splicing. In addition to their anti-angiogenic and pro-apoptotic property, inhibition of the spliceosome can lead to splicing alterations resulting in production of neoepitopes increasing the immunogenicity of tumors. Our hypothesis is that a molecule combining HDAC and spliceosome inhibition could overcome the resistance of anti-PD-1 immunotherapy in a murine lung cancer model TC-1.The molecule Ni313 was evaluated by proteomics as specific for HDAC6 and upregulating the expression of proteins involved in apoptosis, thus demonstrating the induction of cell death. The immunogenic power of cell death (ICD) induced by Ni313 on TC-1 was verified in vivo. The therapeutic power of Ni313 was tested intratumorally on immunocompetent mice. At a dose of 0.5 mg/kg, 50 to 70% treated wild-type mice show complete tumor regression. Mice in remission show long-term protection, reflecting the establishment of a memory and T cell- dependent response, analyzed by flow cytometry in the tumor infiltrate. Immune phenotyping reveals an increase in the level of infiltrating neutrophils in treated mice, confirming the establishment of the ICD. In parallel, spliceosome inhibition was evaluated in vitro, showing the expression of the SIINFEKL peptide contained in an intronic sequence. After a peptidomic study, no specific immunogenic sequence of MHC-I was identified on TC-1. Finally, a combination Ni313/anti-PD-1 therapy was tested, failing to demonstrate the restoration of the effect of immunotherapy. The therapeutic effect of Ni313 is effective as monotherapy by acting on the activity of HDACs inducing cell death by ICD thus provoking an anti-tumor immune response mediated by CD4+ T lymphocytes
Pochard, Pierre. "Immuno-modulation de la réponse allergique par les bactéries lactiques : implications des cellules présentatrices d'antigènes." Lille 2, 2003. http://www.theses.fr/2003LIL2MT09.
Повний текст джерелаRichieri, Raphaëlle. "Substrats neuro-fonctionnels de la stimulation magnétique transcrânienne répétitive dans la dépression pharmaco-résistante." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5026.
Повний текст джерелаTreatment-resistance is a common outcome of a major depressive episode. Repetitive transcranial magnetic stimulation has been put forward as a new technique to treat this debilitating illness. The first objective of our thesis was to characterize the functional substrates of treatment-resistant depression (TRD) using SPECT technique, in order to identify specific patterns of brain abnormalities. In a second part, based on existing work on the antidepressant mechanisms of rTMS, we investigated the predictive value of two neurofunctional biomarkers: SPECT and EEG. Finally, we studied brain SPECT perfusion changes underlying therapeutic efficiency and improvement of quality of life, as currently recommended. Our results showed the existence of a common pattern of brain perfusion in treatment-resistant patients involving the fronto-temporal regions and the cerebellum, regardless the type of depression. At baseline, SPECT brain perfusion and alpha EEG band power could predict individual clinical improvement in TRD-patients treated with rTMS. Regardless the stimulated side, the antidepressant efficacy of rTMS consisted in similar changes in cerebral perfusion. Finally, our results have identified distinct dysfunctional brain regions and confirm the interest of a complementary approach to depression, by assessing quality of life
Rulleau, Caroline. "Caractérisation des réponses contre des antigènes spécifiques aux tumeurs cryptiques pour le développement de thérapies contre les leucémies aiguës." Thesis, 2020. http://hdl.handle.net/1866/25200.
Повний текст джерелаThe treatment of acute myeloid and lymphoblastic leukemia has seen significant advances in the past decade. Despite this progress, the relapse rate remains high and the medical need is real. These leukemias are characterized by an aberrant expression of antigens, some from mutated proteins but also from sequences of DNA that were reported as non-coding. Responses against these “cryptic” neoantigens remains uncharacterized. In order to verify whether a diverse repertoire of T cell receptors (TCR) does recognize these neoantigens, mononuclear cells from peripheral blood of healthy patients are isolated and enriched with naive CD8+ T cells. The expansion and activation of these cells are then carried out with autologous dendritic cells loaded with the antigen of interest and then sorted using HLA-peptide specific multimers. RNA from cells with TCR specific for leukemic tumor-specific antigens (TSA) is isolated in order to perform TCR-beta sequencing. Cell expansion was sufficient to perform the sequencing of cells identified as positive by staining with dextramers. A T-cell response is obtained for 50% of the neoantigens tested with reactivity shown by ELISpot and resulting in a secretion of inflammatory cytokines. T lymphocytes specific to the TSA of interest are therefore present in the peripheral blood of healthy donors. Sequencing of these cells made it possible to identify clonotypes for which a strong anti-leukemic response can be expected. It would be interesting to use these cryptic tumor-specific clonotypes in the development of new adoptive immunotherapy treatments.