Literatura académica sobre el tema "Protéines de points de contrôle immunitaires"
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Artículos de revistas sobre el tema "Protéines de points de contrôle immunitaires":
Bonnefoy, Nathalie, Daniel Olive y Bernard Vanhove. "Les futures générations d’anticorps modulateurs des points de contrôle de la réponse immunitaire". médecine/sciences 35, n.º 12 (diciembre de 2019): 966–74. http://dx.doi.org/10.1051/medsci/2019193.
Delaunay, M., P. Caron, V. Sibaud, C. Godillot, S. Collot, J. Milia, G. Prévot y J. Mazières. "Toxicité des inhibiteurs de points de contrôle immunitaires". Revue des Maladies Respiratoires 35, n.º 10 (diciembre de 2018): 1028–38. http://dx.doi.org/10.1016/j.rmr.2017.08.006.
Bouchereau, Sarah, Joe-Elie Salem, Anissa Roger, Pauline Bonnet, Christine Longvert, Astrid Blom, Amélie Gantzer et al. "Myocardites sous inhibiteurs de points de contrôle immunitaires (ICI)". Annales de Dermatologie et de Vénéréologie - FMC 1, n.º 8 (diciembre de 2021): A195—A196. http://dx.doi.org/10.1016/j.fander.2021.09.118.
Lazarou, Ilias y Eugenio Fernandez. "Complications rhumatologiques des inhibiteurs de points de contrôle immunitaires". Revue Médicale Suisse 16, n.º 685 (2020): 504–7. http://dx.doi.org/10.53738/revmed.2020.16.685.0504.
Dubois, Manon, Camille Ardin, Fanny André, Arnaud Scherpereel y Laurent Mortier. "L’immunothérapie, une révolution en oncologie". médecine/sciences 35, n.º 12 (diciembre de 2019): 946–48. http://dx.doi.org/10.1051/medsci/2019226.
Lurquin, F., S. M. Constantinescu, J. F. Baurain, R. Furnica y D. Maiter. "Caractéristiques du diabète sucré induit par les inhibiteurs de points de contrôle immunitaires". Annales d'Endocrinologie 82, n.º 5 (octubre de 2021): 334. http://dx.doi.org/10.1016/j.ando.2021.08.218.
Chiossone, Laura y Eric Vivier. "Nouvelles frontières de la lutte contre le cancer". Biologie Aujourd'hui 212, n.º 3-4 (2018): 61–67. http://dx.doi.org/10.1051/jbio/2019011.
Rouvet, Guillaume y Olivier Lambotte. "Toxicité des immunothérapies anti-cancéreuses". médecine/sciences 39, n.º 5 (mayo de 2023): 445–51. http://dx.doi.org/10.1051/medsci/2023066.
Belkoniene, Mhedi, Georges Halabi, Samuel Rotman y Sébastien Kissling. "Inhibiteurs de points de contrôle immunitaires et atteinte rénale : mise au point sur une pathologie émergente". Revue Médicale Suisse 16, n.º 683 (2020): 399–403. http://dx.doi.org/10.53738/revmed.2020.16.683.0399.
Coënon, Loïs, Arthur Battistoni, Agathe Poupée-Beaugé, Stéphanie Germon y Isabelle Dimier-Poisson. "Micro-organismes anti-cancéreux et armement". médecine/sciences 37, n.º 1 (enero de 2021): 47–52. http://dx.doi.org/10.1051/medsci/2020259.
Tesis sobre el tema "Protéines de points de contrôle immunitaires":
Dupaty, Léa. "Evaluation in vivo de protéines immunorégulatrices dérivées de CTLA-4 et de PD-L1 pour leur capacité à inhiber les réponses immunitaires dans le contexte de la thérapie génique musculaire par AAV". Thesis, Normandie, 2018. http://www.theses.fr/2018NORMR133/document.
Gene therapy consist into introducing genetic material into cells to treat genetic disorders. Most gene therapies use viral vectors to carry the gene within target cells. In case of monogenic disorders, adeno-associated viruses (AAV) has become a vector of choice because of its lack of pathogenicity, its large tropism and its capacity to transduce quiescent cells. The use of AAV is approved in Europe to treat a rare lysosomal storage disease and has recently been approved by the FDA to treat a genetic cause of blindness. However, most clinical trials face immune responses directed against AAV components which may be highly immunogenic. This deleterious immunogenicity often lead to the trial failure. In addition, transgenic protein can also be immunogenic, aimaing to the destruction of transduced cells and ultimatly to gene therapy failure. In clinic, immunosuppressive drug remain the only option to counteract unwanted immune responses. These drugs possess infectious and tumorigenic side effects, therefore strategies aiming to rather capable to induce tolerance toward the transgenic protein are being developped and needed. The objectif of this work was to implement a new strategy aiming to study the immunoregulatory and tolerogenic effect of fusion proteins derived from CTLA-4 and PD-L1. We used a murin model recapitulating the immunes responses induced by an AAV coding for an immunogenic model protein, ovalbumin (Ova) presented in previous studies by our group and others. Then, we synthesized AAV coding for our newly designed immunoregulatory protein and injected them into mice along with AAV-Ova. This strategy of vectorized immunoregulation (VIR) allowed to evaluate the intrinsic capacity of each individual proteins to modulate immune responses against Ova directly in vivo. Eventually, this work allow to 1) assess the benefits and limits of the VIR strategy, 2) the deletrious long-term effects of CTLA-4/Fc on central and peripheral Tregs in mice, 3) to demonstrate the interest of new molecules specifically derived from PD-L1/Fc over the immune tolerance through the long-term persistance of Ova transgene
Delage, Laure. "Des déficiences génétiques comme modèles naturels pour l'étude de la régulation des checkpoints immunitaires et la caractérisation des réponses auto-immunes". Electronic Thesis or Diss., Université Paris Cité, 2021. http://www.theses.fr/2021UNIP5190.
Recessive NBEAL2 mutations have been reported in patients with Gray Platelet Syndrome (GPS). This syndrome is characterized by a macro-thrombocytopenia, with platelets lacking alpha-granules, leading to bleeding disorders, often associated with splenomegaly. Thus, NBEAL2 plays a crucial role in the trafficking of alpha-granules in platelets. Moreover, our lab has also described NBEAL2 deficiencies in patients presenting clinical features of the autoimmune lymphoproliferative syndrome, suggesting a role of NBEAL2 in immune homeostasis and tolerance. A broader international cohort of GPS patients has been described, revealing immune system abnormalities (autoimmune diseases, autoantibodies, lymphopenia). If the role of NBEAL2 in the traffic of granules is often investigated, the exact mechanism leading to the development of autoimmune manifestations in GPS patients remains unknown. NBEAL2 belongs to a protein family involved in vesicular trafficking, all of which possess a conserved BEACH domain. Within this BEACH-domain containing proteins family, one of the closest members to NBEAL2 is LRBA. LRBA is involved in the recycling of CTLA-4, an inhibitory immune checkpoint. CTLA-4 plays a crucial role in the regulation of immune responses and tolerance. Recessive mutations of LRBA lead to similar clinical features as partial CTLA-4 deficiency: autoimmunity, lymphocytic infiltrations, and progressive B lymphopenia. Physiologically, LRBA prevents the lysosomal degradation of CTLA-4 and allows its recycling to the membrane. By analogy with LRBA, we investigated the importance of NBEAL2 in immune checkpoints intracellular trafficking and we brought new insights on its role in lymphocytes. Thus, NBEAL2 is a scaffold protein, binding LRBA, and involved in CTLA-4 trafficking as well as in vesicular trafficking in general. This work brings new knowledge to the regulation of CTLA-4 in activated T lymphocytes, a list of new partners for NBEAL2 protein and a new model of vesicular trafficking in which NBEAL2 is involved. Finally, a better understanding of the mechanisms leading to autoimmunity in patients with gray platelets syndrome could lead to better diagnosis and treatment management
Paoletti, Audrey. "Étude des étapes précoces de l’infection par le VIH-1 : identification d’un nouveau point de contrôle immunitaire immunitaire impliquant le récepteur P2Y2 et la protéine NLRP3". Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS240.
In 3 decades infection with the virus of the human immunodeficiency of type 1 (HIV-1) caused over than 34 million deaths and the surge of new multiresistant virus strains require the development of novel antiretroviral strategies.Our laboratories revealed a new signaling pathway involving in the early step of HIV-1 infection, involving a hemichannel (Pannexin-1), a common danger signal (extracellular ATP) and a purinergic receptor (P2Y2). These three cellular events are also players in the immune response; we decided to continue the study of proteins involved in the innate immune response during the early stages of infection by HIV -1.Here we demonstrated during this work a new interaction between the purinergic receptor P2Y2 and protein of the inflammasome NLRP3. We demonstrate that P2Y2-stimulated migration of macrophages is inhibited by NLRP3 inflammasome activation. Conversely, NLRP3-dependent macrophage polarization, interleukin-1 β secretion and pyroptosis are under the control of P2Y2-induced autophagy.Finally, the results suggest that the interaction between NLRP3 and P2Y2 is a new immunological checkpoint that regulates macrophage functions. Following this work, we analyzed the role of this immunological control during infection by HIV -1 and have demonstrated that activation of the inflammasome NLRP3 prevents the activation of the purinergic signaling channel involving ATP, pannexin -1 and the P2Y2 receptor, and which allows the entry of HIV -1 in its target cells. Our research and bring to light the capacity of the NLRP3 inflammasome to represent a new inducible restriction factor of HIV-1.All of this research work highlights the existence in macrophages of a new immune system checkpoint involving NLRP3 protein and P2Y2 receptor and can be modulated in order to develop new therapeutic approaches to fight against the emergence of viruses resistant to conventional retroviral treatments
Duranteau, Marie. "Rôle de la kinase BUBR1 dans le contrôle de la division mitotique et dans la prévention de l’aneuploïdie". Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCC260.
The protein is a key-component of the mitotic surveillance mechanism called the Spindle Assembly Checkpoint which occurs during metaphase-anaphase transition. The SAC is essential in eukaryotes because it ensures the equal transmission of the genetic content between the two future daughter cells. In one aspect of my thesis work, I looked in more detail at the "mitotic timer" function of BubR1, responsible for regulating the basal timing of mitotic division, in Drosophila melanogaster. My results showed that a new Linear motif, localized in the N-terminal domain of BubR1, is involved in the recruitment of Fzy/Cdc20 to kinetochore and consequently in the SAC activation. Moreover, my data provide evidence that the mitotic function of BubR1 is correlated with the level of recruitment of Fzy/Cdc20 to the kinetochore in Drosophila. In the second part, I looked for new partners of BubRI during mitosis. Using Mass Spectrometry, we were able to identify the protein Gnfl as a new BubR1 partner. Moreover, the in vivo analysis of the mitotic phenotype associated with the endogenous loss of Gnfl expression (by Gnfl RNAi expression) has provided new evidence for a role of Gnfl in the spindle microtubules dynamics. Finally, I got interested in the kinase catalytic activity of BubRI which has been so far controversial. I showed by in vitro kinase assays that Drosophila BubRI kinase is indeed catalytically active and that it phosphorylates in vitro two novel substrates, Eip63E and Pontin. Using the same approach as for Gnfl, in vivo phenotypic analysis were carried out in ARNi expressing neuroblasts and preliminary data show defects in the mitotic spindle assembly. Altogether, my data has provided novel insights to better understand the "mitotic timer" function of BubR1 as well as its SAC function during mitosis via the identification of novel BubRI partners and substrates
De, Vries-Brilland Manon. "Caractérisation du microenvironnement immunitaire des carcinomes papillaires du rein". Electronic Thesis or Diss., Angers, 2023. http://www.theses.fr/2023ANGE0017.
Article 1: Checkpoint inhibitors in metastatic papillary renal cell carcinoma : papillary Renal Cell Carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC) and a distinct entity, although heterogenous, associated with poor outcomes. The treatment landscape of metastatic pRCC (mpRCC) relied so far on targeted therapies, mimicking previous developments in metastatic clear-cell renal cell carcinoma. However, antiangiogenics as well as mTOR inhibitors retain only limited activity in mpRCC. As development of immune checkpoint inhibitors (ICI) is now underway in patients with mpRCC, we aimed at discussing early activity data and potential for future therapeutic strategies in monotherapy or combination. Expression of immune checkpoints such as PD-L1 and infiltrative immune cells in pRCC could provide insights into their potential immunogenicity, although this is currently poorly described. Based on retrospective and prospective data, efficacy of ICI as single agent remains limited. Combinations with tyrosine-kinase inhibitors, notably with anti-MET inhibitors, harbor promising response rates and may enter the standard of care in untreated patients. Collaborative work is needed to refine the molecular and immune landscape of pRCC, and pursue efforts to set up predictive biomarker-driven clinical trials in these rare tumors. Article 2 : Comprehensive analyses of immune tumor microenvironment in papillary renal cell carcinoma. Background : papillary Renal CellCarcinoma (pRCC) is the most common non-clear cell RCC (nccRCC), and associated with poor outcomes in the metastatic setting. In this study, we aimed to comprehensively evaluate the immune tumor microenvironment (TME) ,largely unknown, of patients with metastatic pRCC and identify potential therapeutic targets. Methods : we performed quantitative gene expression analysis of TME using MCP-counter methodology, on 2 independent cohorts of localized pRCC (n=271 and n=98). We then characterized the TME, using immunohistochemistry (n=38) and RNA-sequencing (RNA-seq) (n=30) on metastatic pRCC from the prospective AXIPAP trial cohort. Results: unsupervised clustering identified 2 "TME subtypes", in each of the cohorts : the “immune-enriched” and the “immune-low”.Within AXIPAP trial cohort, the “immune-enriched” cluster was significantly associated with a worse prognosis according to the median overall survival to 8 months (95%CI, 6-29) versus 37 months (95%CI, 20-NA,p=0.001).The 2 immune signatures, Teff and JAVELIN Renal 101 Immuno signature, predictive of response to immune checkpoint inhibitors (CPI) in ccRCC, were significantly higher in the “immune-enriched” group (adjusted p<0.05). Finally, 5 differentially overexpressed genes were identified, corresponding mainly to B lymphocyte populations. Conclusion : for the first time, using RNA-seqand IHC, we have highlighted a specific immune TME subtype of metastatic pRCC, significantly more infiltrated with T and Bimmune population. This “immune-enriched” group appears to have a worse prognosis and could have a potential predictive value for response to immunotherapy, justifying the confirmation of these results in a cohort of metastatic pRCC treated with CPI and incombination with targeted therapies
Balança, Camille-Charlotte. "Contribution des réponses immunitaires adaptatives spécifiques des antigènes tumoraux à l'efficacité clinique de l'immunothérapie par inhibition de l'axe PD-1/PD-L1". Thesis, Toulouse 3, 2021. http://www.theses.fr/2021TOU30007.
Exhausted tumor-infiltrating lymphocytes (TILs) are characterized by immune checkpoint (IC) expression, for instance PD-1. One of the major immunotherapy approaches, based on IC inhibition, has proved efficient in the control of tumor progression in many cancers. Despite this progress, only a proportion of patients experience clinical benefit. To improve responses to IC inhibitors, understanding mechanisms involved in TIL exhaustion and investigating which T cells are able to respond to immunotherapy are required. We investigated both CD8 and CD4 T-cell exhaustion and its relation to tumor antigen (Ag) specificity and to responsiveness to IC inhibition in cancer patients. We demonstrated that CD8 T-cell exhaustion at the tumor site was only attained by tumor Ag-specific cells that were characterized by the sequential acquisition of ICs and by CD28 loss. Their circulating counterparts expressed less ICs and at lower levels and were CD28+. Specific CD8 TILs were dysfunctional, nonetheless, they maintained high cytotoxic potential and expressed tissue residency markers. We showed that PD-1 inhibition has a dual effect on specific CD8 T cells. It rescued their effector functions at the tumor site and enhanced their proliferation in the periphery. Importantly, the quantity of exhausted and specific TILs was predictive of response to therapy and of survival in patients treated with PD-1-targeting immunotherapy. Assessment of CD4 TIL exhaustion underscored similarities with the CD8 exhaustion program, in particular their specificity for tumor Ag and sequential acquisition of ICs although ICs characterizing terminally exhausted CD4 TILs were different than those found in CD8 TILs. Importantly, PD-1 blockade on CD4 TILs restored their helper functions, leading to dendritic cell maturation and, consequently, increased tumor-specific CD8 T-cell proliferation. Our data imply that under anti-PD-1/PD-L1, effector functions of terminally exhausted CD8 TILs is rescued and the tumor site is replenished by memory CD8 T cells which proliferate following direct blockade of PD-1 and through reinvigoration of the helper activity of tumor Ag-specific CD4 T cells. Our results position tumor Ag-specific T cells as major players of responsiveness to PD-1-blocking immunotherapy and identify predictive biomarkers of response to immunotherapy
Grosjean, Iris. "SQSTM1, une protéine de plateforme à la croisée de la réponse aux dommages à l’ADN et de la réponse à l’immunothérapie dans le cancer : rôles des rétrovirus endogènes". Electronic Thesis or Diss., Université Côte d'Azur, 2020. http://www.theses.fr/2020COAZ6037.
Non-small cell lung cancer (NSCLC) is the deadliest cancer in the world, due to acquired resistance to genotoxic chemotherapy and radiotherapy (DNA-damaging agents, named DDAs hereafter) and targeted therapies. Immunotherapy (including immune checkpoint inhibitors (ICIs)) is a real revolution in patient care. This strategy has indeed had a positive impact, turning into treatable advanced cancers without "actionable" targets that were considered incurable. Survival at 5-year has increased from 5% with conventional treatment to 20% with immunotherapies and up to 50/60% for melanoma and lung cancer with therapies combining ICIs and DDAs. The current challenge in clinical trials is to develop combined therapeutic strategies that increase efficacy while limiting resistance to different treatments. Elucidating resistance mechanisms is essential to propose new robust predictive biomarkers and new therapeutic approaches to improve the efficacy of ICIs.We have hypothesized that resistance to DDAs and ICIs is mediated by intrinsic tumor mechanisms, some of which may be shared. Thus, we have studied the action of DDAs and their molecular consequences that lead to immune evasion. Through three complementary approaches (in silico, in vivo on patient cohorts and in vitro), we identify the p62/SQSTM1 scaffold protein as a key molecular mediator capable of predicting and controlling sensibility to DDAs and ICIs. We report for the first time that SQSTM1 causes a "HOT" tumor immune profile, while downregulating DNA repair mechanisms. In addition, SQSTM1 is essential for the DDAs-induced reactivation of human endogenous retroviruses (hERVs). Downstream, hERVs induce an innate antiviral response, resulting in the expression of interferons, MHC-I and PD-L1, leading to tumor immune evasion.In conclusion, i) we propose SQSTM1 as a predictive biomarker for selecting patients who may benefit from ICI plus DDA combination strategies, and ii) we highlight a biological rationale for the efficacy of such strategies in refractory lung cancer, aimed at promoting their use and thus improving the prognosis of NSCLC
Mailhat, Charlotte. "Etudes des modifications post-traductionnelles de la phosphatase Cdc25C lors de la régulation de la transition G2/M du cycle cellulaire". Toulouse 3, 2007. http://www.theses.fr/2007TOU30310.
CDC25C phosphatase is a key actor in cell cycle progression that controls the activation of CDK1-cyclin B at mitosis and during the G2/M DNA damage. Its activity is known to be highly regulated by a number of signalling pathway-activated kinases resulting in its phosphorylation on multiple residues. In this study, we have purified CDC25C from cells and have used a proteomic approach to identify new regulatory phosphorylations. Here, we report the identification by mass spectrometry of two phosphorylations on serine 168 and 263, and one méthylation on arginine 35. To conclude we have realized a functional analysis of S168 and S263 phosphorylations. We demonstrate by cell imaging that mutation of S263 to alanine leads to a nuclear accumulation of CDC25C. We propose that phosphorylation at S263 is part of the regulatory mechanism that modulates nuclear import of CDC25C, thus preventing cytoplasm to nucleus shuttling
Xie, Wei. "Transcription Inhibitor Lurbinectedin and Oncolytic Peptide LTX-401 trigger Immunogenic Cell Death and Synergize With Immune Checkpoint Blockade Lurbinectedin Synergizes With Immune Checkpoint Blockade To Generate Anticancer Immunity Tumor Lysis With LTX-401 Creates Anticancer Immunity Autophagy Induction by Thiostrepton Improves the Efficacy of Immunogenic Chemotherapy Oncolysis With DTT-205 and DTT-304 Generates Immunological Memory in Cured Animals". Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL072.
Cancer is the second leading cause of death worldwide, despite the existence of standard treatment, innovative therapeutic strategies and drugs are still in urgent demand. The combination of immunogenic cell death (ICD) inducing drugs and immune checkpoint blockade (ICB) seems to be a promising modality. In this thesis, we demonstrated Lurbinectedin, a transcription inhibitor newly approved for relapsed lung cancer treatment, triggers hallmarks of ICD in four different human and murine cell lines in vitro. Vaccinated with Lurbinectedin-treated fibrosarcoma cell protects immunocompetent mice from rechallenge with syngeneic tumours. Lurbinectedin restrains transplanted fibrosarcoma growth in an immune dependent manner. Both transplanted MCA205 cancer and hormone/carcinogen induced breast cancer were sensitized by Lurbinectedin to PD-1 and CTLA-4 double ICBs. Of note, long-term immunological memory was generated in cured mice. Further, we evaluated the anticancer capacity of LTX-401, an oncolytic peptide designed for local immunotherapy. Sequential intratumoral injections of LTX-401 dramatically retards subcutaneous MCA205 and TC-1 tumour growth in immunocompetent host, yet shows limited therapeutic effect of anti-CTLA-4 or anti-PD-1/anti-CTLA-4 ICBs. Moreover, sequential LTX-401 treatment with double ICBs exhibits systemic antitumor immunity to both treated and abscopal tumour. In conclusion, lurbinectedin and LTX-401 induce cancer cell immunogenic cell death and enhance the anticancer effects of immune chekcpoint blockade. These results lay the experimental foundation of combination regiments and may facilitate the clinical trial design
Batnini, Kalil. "Rôles de la protéine E4F1 dans le contrôle de la réponse aux dommages de l’ADN dans le cancer du sein triple négatif". Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT003.
The E4F1 protein discovered as the cellular target of the adenoviral oncoprotein E1A is a ubiquitous protein acting both as a transcription factor and as an atypical E3-ligase. E4F1 protein also interacts directly with several cellular tumor suppressors and oncoproteins, suggesting its involvement in tumorigenesis. Previous laboratory work on the cellular functions of E4F1 in cancer cells has shown that its depletion leads to massive cell death in transformed Mefs deficient in p53. In addition, E4F1 directly controls the expression of 38 genes, including genes involved in cell metabolism and cell cycle checkpoints/DNA Damage Response (DDR), such as Chek1 that encodes a major component of the ATR/ATM checkpoint. Consistent with this role of E4F1 in cancer cell survival in mice, patients with triple-negative breast cancer (TNBC) with high E4F1 expression exhibit a poorer relapse free survival (RFS).We therefore aimed to study for the first time the transcriptional program of E4F1 in human cells and explore its role in the survival of TNBC cells, with particular focus on its role in the response to chemotherapy agents.Transcriptomes (RNAseq) of SUM159 TNBC cells show, when E4F1 is depleted, a decrease in expression of 147 out of 276 DDR-associated genes. The combination of RNAseq and ChIPseq shows that E4F1 directly regulates 57 genes in human TNBC cells. Among these genes, E4F1 itself, CHEK1, but also TTI2 and PPP5C coding for post-transcriptional regulators of the ATM/ATR-CHK1 axis, and thus defining an ATM/ATR-CHK1 "regulon", undescribed and E4F1-dependent. TTI2 composes with TELO2 and TTI1, the TTT complex required for the correct folding and stability of PIKK family proteins, such as ATR and ATM. PPP5C phosphatase is involved in the activation of ATR-CHK1 signaling. Importantly, we show that E4F1 binds to and probably regulates these three genes in vivo in Patient Derived TNBC Xenografts (PDTX). In both SUM159 cells and PDTX, the recruitment of E4F1 on these genes is increased upon Gemcitabine treatment, a chemotherapy agent that impairs DNA replication. Surprisingly, we found that E4F1 also indirectly controls the expression of TELO2, a second member of the TTT complex. Consequently, in TNBC cells depleted of E4F1, the protein levels of CHK1, TTI2, TELO2 but also ATM/ATR kinases, are significantly decreased, leading to DDR deficiency. Thus, SUM159 cells depleted of E4F1 fail to stop in phase S during Gemcitabine treatment and are highly sensitized to this chemotherapy agent, as well as other DNA damaging agents such as Cisplatin. Altogether, my thesis results demonstrate that the ATM/ATR-CHK1 signaling pathway, and the response to stress / DNA damage are tightly controlled at the transcription and post-transcription levels by E4F1. E4F1 therefore appears to be a central actor in the cellular survival of TNBC cells, particularly when exposed to DNA-damaging agents or chemotherapy agents. Thus, E4F1 could represent a prognostic marker for chemotherapy response and a potential therapeutic target