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Strategies of Cancer Immunotherapy: Model of Triple Negative Breast Cancer

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Strategies of Cancer Immunotherapy: Model of Triple Negative Breast Cancer Strategies of Cancer Immunotherapy : Model of Triple Negative Breast Cancer Masae Kishi To cite this version: Masae Kishi. Strategies of Cancer Immunotherapy : Model of Triple Negative Breast Cancer. Cancer. Université Paris Saclay (COmUE), 2019. English. NNT : 2019SACLS070. tel-02527172 HAL Id: tel-02527172 https://tel.archives-ouvertes.fr/tel-02527172 Submitted on 1 Apr 2020 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. Strategies of Cancer Immunotherapy: Model of Triple Negative Breast Cancer NNT: 2019SACLS070 NNT: Thèse de doctorat de l'Université Paris-Saclay Préparée à l’Université Paris-Sud École doctorale n°582 : cancérologie : biologie - médecine - santé (CBMS) Spécialité de doctorat : Sciences de la vie et de la santé Thèse présentée et soutenue à Villejuif, le 15 mars 2019, par Masae KISHI HERONT Composition du Jury : Fawzia LOUACHE Professeur, Université Paris-Saclay (INSERM U1170) Président Anne CAIGNARD Directeur de Recherche, Institut Cochin (INSERM U1016) Rapporteur Christelle MONVILLE Professeur, I-STEM (INSERM / UEVE U861) Rapporteur Franck PAGES Professeur, Université Paris Descartes (INSERM U1138) Examinateur Virginie DANGLES-MARIE Maître de Conférences, Institut Curie Examinateur Frank GRISCELLI Professeur, Université Paris Descartes (INSERM U935) Directeur de thèse Annelise BENNACEUR GRISCELLI Professeur, Université Paris Sud / Paris Saclay (INSERM U935) Co-Directeur de thèse TABLE OF CONTENTS Abstract ··········································································································· a List of figures ··································································································· c List of tables ···································································································· e List of annexes ··································································································· g Abbreviations ·································································································· i Acknowledgements ···························································································· k INTRODUCTION ······························································································ 1 1 Chapter 1: Triple Negative Breast Cancer ······························································ 1 1.1 Human Mammary gland ·········································································· 1 1.2 Epidemiology of breast cancer ··································································· 2 1.3 Classification of breast cancer ··································································· 3 1.3.1 Molecular subtypes of breast cancer ······················································ 5 1.3.2 Triple negative breast cancer (TNBC) and Basal-like subtype ························ 9 1.3.3 Immune system and TNBC ······························································· 10 1.4 Breast cancer stem cells ········································································· 13 1.4.1 Cancer Stem Cell (CSC) ·································································· 13 1.4.2 Embryonic stem cell-like gene signature in TNBC ··································· 15 1.4.3 Stemness molecular profile in breast cancer ··········································· 19 1.4.4 Breast cancer stem cells ··································································· 24 1.4.5 Tumor evolution of TNBC ······························································· 25 1.5 Treatment for TNBC············································································· 28 2 Chapter 2: Immunity and cancer ······································································ 32 2.1 Tumor microenvironment (TME) ······························································ 34 2.1.1 Overview ···················································································· 34 2.1.2 Immune context in breast cancer ······················································· 37 2.2 Inflammation and cancer ········································································ 38 2.3 Innate immunity ·················································································· 39 2.3.1 Macrophages ··············································································· 41 2.3.2 Dendritic cells ·············································································· 41 2.3.3 Myeloid-derived suppressor cells (MDSC) ············································ 42 2.3.3.1 Murine MDSCs ···································································· 44 2.3.3.2 Human MDSCs ···································································· 44 2.3.3.3 MDSC infiltration in tumor ······················································ 44 2.3.3.4 Mechanisms of immunomodulatory functions by MDSCs ·················· 45 2.3.3.5 MDSC triggers tumor metastasis ················································ 46 2.3.3.6 Re-education potential of MDSCs ·············································· 46 2.3.4 NK cells ····················································································· 47 2.4 Adaptive immunity ·············································································· 48 2.4.1 T cells ························································································ 49 2.4.1.1 Cytotoxic T lymphocyte (CTL) ·················································· 51 2.4.1.2 Regulatory T cells ································································· 53 2.4.1.2.1 Differentiation of Tregs ··················································· 53 2.4.1.2.2 Function of Tregs ·························································· 54 2.4.1.2.3 nTregs and iTregs in cancer ·············································· 55 2.4.1.3 Helper T cells ······································································ 56 2.4.1.3.1 Type 1 helper T (Th1) cells ·············································· 56 2.4.1.3.2 Type 2 helper T (Th2) cells ·············································· 57 2.4.1.3.3 T helper 9 (Th9) and T helper 17 (Th17) cells ························ 58 2.4.1.3.4 Plasticity of helper T cells ················································ 58 2.4.1.3.5 TCR signal strength in mature T cell differentiation ················· 58 2.4.1.4 T cell memory ······································································ 59 2.4.1.5 Cross reaction, allo/xeno reaction by T cells ·································· 60 1.1.1.1.1 Reactions against allo/xeno products ··································· 60 1.1.1.1.2 Structural evidences ······················································· 61 2.4.2 B cells ······················································································· 62 2.5 Cytokines ·························································································· 63 2.6 Chemokines ······················································································· 64 3 Chapter 3: Cancer immunotherapy ···································································· 67 3.1 History ····························································································· 67 3.2 Therapeutic approaches ········································································· 69 3.2.1 Cytokines and Vaccines ··································································· 69 3.2.1.1 Protein/peptide-based vaccines ·················································· 70 3.2.1.2 DNA/RNA based vaccines ······················································· 71 3.2.1.3 Viral based vaccines ······························································· 71 3.2.1.4 Immunological perspective behind cancer vaccine ··························· 71 3.2.2 Adoptive cell therapy ······································································ 72 3.2.2.1 Chimeric antigen receptor T (CAR T) cells ···································· 73 3.2.3 Immune check point inhibitors ··························································· 74 3.2.3.1 Anti-CTLA4 antibodies ··························································· 79 3.2.3.2 Anti-PD1/PDL1 antibodies ······················································· 79 3.3 Cancer antigens ·················································································· 80 3.3.1 Tumor-associated antigens (TAAs)······················································ 81 3.3.2 Differentiation antigens ··································································· 81 3.3.3 Cancer/testis antigens (CTAs) ···························································· 81 3.3.4 Oncofetal antigens ········································································· 81 3.3.5 Tumor specific antigens (TSAs) ························································· 84 3.3.6 Neo-antigens (mutant peptides or protein) ············································· 84 3.4 Vaccine adjuvants and immune response modifiers
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