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Influence of Hypoxia on Tumour Cell Susceptibility to Cytotoxic T Lymphocyte Mediated Lysis Muhammad Zaeem Noman

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Influence of Hypoxia on Tumour Cell Susceptibility to Cytotoxic T Lymphocyte Mediated Lysis Muhammad Zaeem Noman Influence of hypoxia on tumour cell susceptibility to cytotoxic T lymphocyte mediated lysis Muhammad Zaeem Noman To cite this version: Muhammad Zaeem Noman. Influence of hypoxia on tumour cell susceptibility to cytotoxic Tlympho- cyte mediated lysis. Cancer. Université Paris Sud - Paris XI, 2012. English. NNT : 2012PA11T051. tel-01024170 HAL Id: tel-01024170 https://tel.archives-ouvertes.fr/tel-01024170 Submitted on 24 Nov 2014 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITE PARIS XI INSERM U753 Institut Gustave Roussy FACULTE DE MEDECINE PARIS-SUD 114, rue Edouard Vaillant 94805 Villejuif THESE Pour obtenir le grade de DOCTEUR DE L’UNIVERSITE PARIS XI Ecole Doctorale de Cancérologie Discipline : Cancérologie Présentée par Muhammad Zaeem NOMAN Influence of hypoxia on tumor cell susceptibility to cytotoxic T lymphocyte mediated lysis Influence de l’hypoxie sur la susceptibilité des cellules tumorales à la lyse induite par les lymphocytes T cytotoxiques Soutenue le 28 septembre 2012 devant le jury composé des : Prof. Eric SOLARY Président Dr. Nathalie MAZURE Rapporteur Prof. Daniel OLIVE Rapporteur Dr. Bernard MARI Examinateur Dr. Salem CHOUAIB Directeur de thèse ABSTRACT Hypoxia is a common feature of solid tumors and one of the hallmarks of tumor microenvironment. Tumor hypoxia plays an important role in angiogenesis, malignant progression, metastatic development, chemo-radio resistance and favours immune evasion by the emergence of tumor variants with increased survival and anti-apoptotic potential. There is very little work done on the impact of tumor hypoxia on the regulation of tumor susceptibility to the lysis induced by cytotoxic antitumor response. Therefore, we asked whether hypoxia confers tumor resistance to cytotoxic T lymphocyte (CTL)-mediated killing. We demonstrated that exposure of target cells to hypoxia has an inhibitory effect on the CTL-mediated autologous target cell lysis. Such inhibition was not associated with an alteration of CTL reactivity and tumor target recognition. We also showed that the concomitant hypoxic induction of Signal transducer and activator of transcription 3 (STAT3) phosphorylation on tyrosine 705 residue (pSTAT3) and hypoxia inducible factor 1 alpha (HIF-1α) is functionally linked to the alteration of Non small cell lung carcinoma (NSCLC) target susceptibility to CTL- mediated killing. We also showed that hypoxia-induced resistance of lung tumor to CTL-mediated lysis was associated with autophagy induction in target cells. Inhibition of autophagy resulted in impairment of pSTAT3 (via inhibition Src kinase) and restoration of hypoxic tumor cell susceptibility to CTL-mediated lysis. Moreover, in vivo inhibition of autophagy by hydroxychloroquine (HCQ) in B16F10 tumor bearing mice and mice vaccinated with TRP2 peptide dramatically increased tumor growth inhibition. Collectively, the current study establishes a novel functional link between hypoxia-induced autophagy and the regulation of antigen specific T cell lysis and points to a major role of autophagy in the control of in vivo tumor growth. Finally, as resistance of tumor targets to killer cells is likely to be regulated by multiple factors, we further aimed to identify the microRNA’s regulated by hypoxia in NSCLC and melanoma and their putative involvement in the regulation of tumor susceptibility to antigen-specific CTL-mediated killing. MicroRNA-210 (miR-210) was significantly induced in a HIF-1α dependent manner in NSCLC and melanoma cells and miR-210 was expressed in hypoxic zones of human NSCLC tissues. Moreover, we demonstrated that hypoxia-induced miR-210 regulates tumor cell susceptibility to CTL-mediated lysis in part by suppressing PTPN, HOXA1 and TP53I11 expression indicating that miR-210 plays a potential role in the regulation of anti-tumor immune response. TABLE OF CONTENTS LIST OF FIGURES ______________________________________________________________ 3 LIST OF TABLES _______________________________________________________________ 4 LIST OF ABBREVATIONS ________________________________________________________ 5 ACKNOWLEDGEMENTS ________________________________________________________ 7 PREFACE ____________________________________________________________________ 11 INTRODUCTION ______________________________________________________________ 12 I. HYPOXIA _______________________________________________________________ 12 A. History of research on hypoxia __________________________________________________ 12 B. Tumor Hypoxia _______________________________________________________________ 15 1. Normoxic, hypoxic and necrotic zones __________________________________________________ 15 2. Types of tumor hypoxia ______________________________________________________________ 17 a. Acute/transient or perfusion-limited hypoxia _________________________________________ 17 b. Chronic or diffusion-limited hypoxia _________________________________________________ 18 c. Acute versus chronic hypoxia _______________________________________________________ 18 3. Hypoxia inducible factors (HIF’s) as master regulators of adaptation to hypoxia________________ 19 4. Molecular Biology of HIF family _______________________________________________________ 19 5. Structure of Hypoxia inducible factors __________________________________________________ 20 6. Oxygen dependent regulation of HIFα __________________________________________________ 21 a. Role of prolyl hydroxylase domain in the regulation of HIFα protein degradation ____________ 21 b. Role of factor-inhibiting HIF (FIH) in the regulation of HIFα transactivation _________________ 22 7. Oxygen independent regulation of HIFα (pseudo hypoxia or hypoxia like normoxia) ____________ 24 a. The tumor suppressor gene LOF contributes to increased levels of HIFα ___________________ 26 b. Regulation of HIF-1 activity by oncoproteins __________________________________________ 26 8. Diverse factors which regulate HIFα ____________________________________________________ 27 C. Hypoxia (HIF-1α and HIF-2α) and cancer __________________________________________ 29 1. Clinical data linking HIF-1α and HIF-2α levels to patient mortality ___________________________ 29 2. Role of HIF-1α and HIF-2α in cancer progression _________________________________________ 30 3. Effects of genes regulated by HIFs on different aspects of cancer biology _____________________ 31 4. Gene expression regulation by HIF-1α and HIF-2α ______________________________________ 33 5. Hypoxia (HIF-1α, HIF-2α) and p53 ______________________________________________________ 35 D. Detection and measurement of tumor hypoxia ____________________________________ 36 II. Hypoxia: a key player in tumor microenvironment ____________________________ 38 A. Hypoxia increases resistance to cytotoxic drugs __________________________________________ 40 B. Hypoxia increases cell proliferation and survival _______________________________________ 41 C. Hypoxia: pro-survival versus pro-cell death? __________________________________________ 42 III. HIF inhibitors for cancer therapy ___________________________________________ 43 A. Upstream targets of HIF ________________________________________________________ 45 B. Direct targets of HIFs (HIF-1α and HIF-2α) _________________________________________ 45 1. HIF-α antisense, dominant negative HIF-α and viral vectors ________________________________ 45 2. Small molecules that inhibit HIF at multiple sites _________________________________________ 46 C. Downstream targets of HIF _____________________________________________________ 46 D. HIF-1α vs HIF-2α targeting? _____________________________________________________ 46 E. Can HIF inhibitors improve current therapies? _____________________________________ 47 1 IV. Anti-tumor immune response ____________________________________________ 48 A. Cancer Immuno-surveillance theory _____________________________________________ 48 1. Experimental studies ________________________________________________________________ 49 2. Clinical evidence ____________________________________________________________________ 49 B. The cancer Immuno-editing hypothesis ___________________________________________ 49 C. The antitumor immune response ________________________________________________ 52 1. The adaptive immune response _______________________________________________________ 54 a. CD4+ T cells______________________________________________________________________ 54 b. CD8+ T cells (Cytotoxic T lymphocyte) ________________________________________________ 56 c. CTL killing mechanisms ____________________________________________________________ 56 d. The immunological synapse (IS) _____________________________________________________ 58 i. Formation of the immunological synapse __________________________________________ 58 ii. The lytic synapse (polarization of lytic granules) _____________________________________ 60 e. Mechanism of cytotoxic granule killing _______________________________________________ 62 f. Death domain receptor-mediated killing _____________________________________________
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