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Etude des réponses lymphocitaires T spécifiques de néoantigènes tumoraux après immunomodulations induites par des chimiothérapies

Abstract : The current theory of cancer immunosurveillance establishes the existence of a dynamic system o interaction between the immune system and tumor cells. Several major experiments have demonstrated th importance of the immune system and in particular T cells in cancer surveillance and the effectiveness of anti tumor therapies. Treatments used against cancer can stimulate or inhibit the immune response to tumor. I addition to their cytotoxic effect on cancer cells, these drugs, such as Sorafenib, can inhib' immunosuppressive cells such as Treg and MDSC. Other chemotherapies, such as Oxaliplatin, can induce a immunogcnic cell death required for its efficacy. Oxaliplatin is a1so known to add alkyl groups on the puri bases that cause DNA mutations. At the same titne, the characterization of many immunogenic mutations ha been carried out in recent years without evaluating the role of treatments in the appearance of suc immunogenic mutations. The specific mutations of the alkylating agents correspond to a modification of th AG, GG bases and 5' base of the AG or GG motif. These mutations would diversify the antigenic repertoire b creating neo-antigens recognized by T cells. The main objective of this work was to identify new immunogenic epitopes derived from tumor antigens using a reverse immunology strategy. The first part identified three immunogenic neoepitopes restricted by MHC-11 and potentially involved in the complete remission of a patient with metastatic hepatocarcinoma treated with Sorafenib. The immunogenicity of these three neoepitopes derived from mutated HELZ2, MLL2 and IL-1The main objective of this work was to identify new immunogenic epitopes derived from tumor antigens using a reverse immunology strategy. The first part identified three immunogenic neoepitopes restricted by MHC-11 and potentially involved in the complete remission of a patient with metastatic hepatocarcinoma treated with Sorafenib. The immunogenicity of these three neoepitopes derived from mutated HELZ2, MLL2 and IL-1β proteins was validated after in vitro stimulation of the patient's T cells. The second pati, dealing with the identification of neoantigens induced by Oxaliplatin, made it possible to characterize chemoinduced mutations and to identify 26 neoepitopes potentially presented by MHC-I. This work reinforces the link between the immune system and the effectiveness of chemotherapy. The suggest for the first time that chemotherapy could increase tumor immtmogenicity by increasing the repertoir of neo-antigens. proteins was validated after in vitro stimulation of the patient's T cells. The second pati, dealing with the identification of neoantigens induced by Oxaliplatin, made it possible to characterize chemoinduced mutations and to identify 26 neoepitopes potentially presented by MHC-I. This work reinforces the link between the immune system and the effectiveness of chemotherapy. The suggest for the first time that chemotherapy could increase tumor immtmogenicity by increasing the repertoir of neo-antigens.
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Submitted on : Tuesday, September 11, 2018 - 2:18:06 PM
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Sindy Vrecko. Etude des réponses lymphocitaires T spécifiques de néoantigènes tumoraux après immunomodulations induites par des chimiothérapies. Immunologie. Université Bourgogne Franche-Comté, 2018. Français. ⟨NNT : 2018UBFCE001⟩. ⟨tel-01871930⟩

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