Publicação
Influence of HOXA9 in the response of glioblastoma to immune checkpoint inhibitors
| Resumo: | Glioblastoma (GBM) is the most common and malignant primary central nervous system (CNS) tumour in adults, characterized by high resistance to conventional therapies and a very poor outcome, with a median survival of 15 months. GBM is a highly immunosuppressive tumour, with mechanisms to promote tumour escape from the immune system. Its microenvironment is characterized by the presence of cytokines that inhibit the immune system by suppressing T-cell activation and proliferation, and skewing the immune cells towards a pro-tumour phenotype. Additionally, GBM cells frequently overexpress programmed cell death ligand 1 (PD-L1), an immune checkpoint ligand that binds to programmed cell death 1 (PD1) present in activated T-cells. Recently, immunotherapies using immune checkpoint inhibitors (ICIs) have gained importance by showing promising results in treatment of various cancers. Previous studies showed that HOXA9, a critical transcription factor deregulated in gliomas, is critical in resistance to standard chemotherapy, and global aggressiveness of GBM. Moreover, HOXA9 down regulates mechanisms related to antigen processing and presentation, and to immune responses. This project aims to decipher the relevance of HOXA9 in the immune evasion in GBM, both in treatment-naïve conditions and under ICIs therapy. For this, HOXA9 over-expression and silencing models of human GBM cell lines were used, to understand whether HOXA9 expression modulates the expression of cytokines and of immune checkpoint ligands, and how it influences T-cell responses in the presence or absence of ICIs. Results with human GBM cell lines suggest that expression of HOXA9 is associated with differential expression of immune related cytokines: namely inversely associates with IL1B expression; and with IL8 expression in GL18 cell line; and also associated with CCL2 expression in U251 cell line. At protein level, the silencing of HOXA9 leads to a decrease in PD-L1 expression and to an increase in the PD-L2 expression in the membrane of U251 cells. Moreover, a minor but significant increased sensitivity to anti PD1 therapy is observed in U251 cells, but not in the other cell lines (U87 and U251). Regarding T-cell survival and subpopulations, namely Tregs, no significant differences were obtained. Overall, this work suggests that HOXA9 might increase immunosuppression in GBM, and that a partially effective immune response against GBM cell lines seems to exist. To further complement and clarify these results, it is essential to evaluate the secretion of these cytokines and chemokine; and to extend this study, in vivo GBM models could clarify the roles of HOXA9 in immune cells infiltration and in survival of mice in treatment-naïve conditions or upon treatment with ICIs. |
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| Autores principais: | Azevedo, Ana Catarina Mesquita |
| Assunto: | Glioblastoma HOXA9 Immunosuppression Immune checkpoint inhibitors Imunossupressão Inibidores de “Checkpoints” imunes |
| Ano: | 2019 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Glioblastoma (GBM) is the most common and malignant primary central nervous system (CNS) tumour in adults, characterized by high resistance to conventional therapies and a very poor outcome, with a median survival of 15 months. GBM is a highly immunosuppressive tumour, with mechanisms to promote tumour escape from the immune system. Its microenvironment is characterized by the presence of cytokines that inhibit the immune system by suppressing T-cell activation and proliferation, and skewing the immune cells towards a pro-tumour phenotype. Additionally, GBM cells frequently overexpress programmed cell death ligand 1 (PD-L1), an immune checkpoint ligand that binds to programmed cell death 1 (PD1) present in activated T-cells. Recently, immunotherapies using immune checkpoint inhibitors (ICIs) have gained importance by showing promising results in treatment of various cancers. Previous studies showed that HOXA9, a critical transcription factor deregulated in gliomas, is critical in resistance to standard chemotherapy, and global aggressiveness of GBM. Moreover, HOXA9 down regulates mechanisms related to antigen processing and presentation, and to immune responses. This project aims to decipher the relevance of HOXA9 in the immune evasion in GBM, both in treatment-naïve conditions and under ICIs therapy. For this, HOXA9 over-expression and silencing models of human GBM cell lines were used, to understand whether HOXA9 expression modulates the expression of cytokines and of immune checkpoint ligands, and how it influences T-cell responses in the presence or absence of ICIs. Results with human GBM cell lines suggest that expression of HOXA9 is associated with differential expression of immune related cytokines: namely inversely associates with IL1B expression; and with IL8 expression in GL18 cell line; and also associated with CCL2 expression in U251 cell line. At protein level, the silencing of HOXA9 leads to a decrease in PD-L1 expression and to an increase in the PD-L2 expression in the membrane of U251 cells. Moreover, a minor but significant increased sensitivity to anti PD1 therapy is observed in U251 cells, but not in the other cell lines (U87 and U251). Regarding T-cell survival and subpopulations, namely Tregs, no significant differences were obtained. Overall, this work suggests that HOXA9 might increase immunosuppression in GBM, and that a partially effective immune response against GBM cell lines seems to exist. To further complement and clarify these results, it is essential to evaluate the secretion of these cytokines and chemokine; and to extend this study, in vivo GBM models could clarify the roles of HOXA9 in immune cells infiltration and in survival of mice in treatment-naïve conditions or upon treatment with ICIs. |
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