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Boosting anti-tumor immune responses by rendering tumor-specific T cells resistant to immunosuppression

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Resumo:Tumor-infiltrating lymphocytes are crucial players in the immunosuppressive tumor microenvironment (TME), as they play a crucial role in anti-tumor immunity. Despite some having pro-inflammatory functions, their responses are not sufficient to ensure a good clinical prognosis. Multiple immunotherapies, therapies that use the immune system by boosting its response to treat tumors, have been thoroughly studied, such as ACT (which includes both CAR T cell therapy and TCR T cell therapy). CAR T cell therapy has shown impressive results in fighting B cell malignancies but still fails in fighting solid tumors and in provoking lasting responses. CAR T cells can only recognize surface antigens, which limits their action. For this reason, there is a need to come up with therapies, such as TCR T, that can access the whole proteome and bypass tumor immunosuppression. With this project, we aimed to understand the role of certain genes in mediating T cell-dependent antitumor immunity. For this, we performed proof-of-principle experiments using tumors expressing a defined, known model antigen (ovalbumin [OVA]). We successfully genetically modified OVA-specific T cells by overexpressing a panel of candidate genes that mediate how T-cells respond to immunosuppression, we also constructed OVA-expressing tumor cell lines (melanoma and adenocarcinoma) and confirmed that they were targeted by OVA-specific T cells. Lastly, our findings suggest that the overexpression of these genes increased cytokine production of T cells and, the T cells overexpressing Adenosine deaminase seem to have a higher resistance to this adenosine-mediated immunosuppression. Therefore, there is still a need for more research on this topic, but our findings suggest a way to render T cells resistant to immunosuppression, which can be helpful in the context of engineered TCR T cell therapy.
Autores principais:Oliveira, Matilde Maria Sá Alves Carviçais de
Assunto:Microambiente tumoral célula T Immunossupressão Engenharia Genética Imunoterapia Teses de mestrado - 2024
Ano:2024
País:Portugal
Tipo de documento:dissertação de mestrado
Tipo de acesso:acesso embargado
Instituição associada:Universidade de Lisboa
Idioma:inglês
Origem:Repositório da Universidade de Lisboa

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