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Boosting anti-tumor immune responses by rendering tumor-specific T cells resistant to immunosuppression
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Orientador(es)
Resumo(s)
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.
Descrição
Tese de mestrado, Bioquímica e Biomedicina , 2024, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Microambiente tumoral célula T Immunossupressão Engenharia Genética Imunoterapia Teses de mestrado - 2024