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Dissecting microenvironment roadblocks to DOT-cell immunotherapy
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Resumo(s)
As células T γδ Vδ1+ são um subgrupo de linfócitos com elevada reatividade tumoral. A sua ativação é independente da carga mutacional do tumor e da apresentação HLA/MHC, permitindo assim a sua aplicação alogénica. Anteriormente, o nosso laboratório desenvolveu um protocolo de expansão e diferenciação de células T γδ Vδ1+ do sangue periférico, criando um produto de imunoterapia denominado células Delta One T (DOT), que está atualmente a ser testado em leucemia mielóide aguda. O nosso objetivo é redirecionar as células DOT para tumores sólidos, em particular cancro do cólon. No entanto, é esperado que alguns obstáculos impostos pelo microambiente dos tumores sólidos diminuam a eficácia das células DOT.
Neste projeto propomos estudar o impacto de duas importantes barreiras que as células DOT podem encontrar no microambiente tumoral: a privação de dois nutrientes. Também pretendemos encontrar estratégias para mitigar as limitações impostas por estes obstáculos.
Demonstrámos que a restrição dos dois nutrientes diminuiu a percentagem de células produtoras de interferão-gama, de granzima/perforina e a sua atividade anti tumoral. É de salientar que um nutriente impactou as células DOT de forma mais significativa que o outro. Também testámos quatro drogas diferentes com o objetivo de reverter o impacto da privação dos nutrientes nas células DOT. A maioria das drogas não conseguiu reverter o fenótipo das células DOT, no entanto, uma das drogas conseguiu reverter parcialmente o efeito da restrição de ambos os nutrientes ao aumentar a expressão de interferão-gama.
Em conclusão, demonstrámos que a disponibilidade de nutrientes no microambiente tumoral diminuiu a capacidade anti tumoral das células DOT e que a incubação destas células com uma droga tem o potencial de reverter parcialmente o efeito da inibição imposta pela restrição de nutrientes. Estas descobertas serão cruciais para desenvolver novos protocolos e melhorar a eficácia das células DOT contra cancro do colón, e potencialmente, outros tumores sólidos.
Vδ1+ γδT cells are a subset of lymphocytes that displays broad tumour reactivity. Critically, their activation is independent of tumour mutational load and of HLA/MHC-presentation, which enables their application in an allogeneic setting. Previously, our lab has developed a clinical-grade protocol to expand and differentiate peripheral blood Vδ1+ γδT cells leading to the generation of an immunotherapeutic product termed Delta One T (DOT) cells – which is currently in clinical trials against chemoresistant Acute Myeloid Leukaemia. We aim to repurpose DOT cells for solid tumours, in particular colon cancer. However, some hurdles imposed by the solid tumour microenvironment (TME) are expected to hamper DOT-cell efficacy. Here we propose to study the impact on DOT-cell function of two well-known TME roadblocks: two different nutrient deprivation. We also aim to find strategies to overcome the limitations imposed by these factors. We demonstrated that restriction of two nutrients dampened DOT-cell interferon-γ (IFN-γ) production, granzyme/perforin expression and decreased its antitumour killing capacity. Importantly, one nutrient impacted DOT cells more severely than the other. We then tested four different drugs to revert the impact of nutrient starvation on DOT cells. While most of them failed to revert the phenotype, we found one drug able to partially revert the effect of both nutrient restrictions by increasing IFN-γ expression. In conclusion, we demonstrate that nutrient availability in the TME decreases the antitumour capacity of DOT cells and we unravel a potential drug that can improve DOT-cell antitumour function. These discoveries will be critical for the design of new protocols to improve the efficacy of DOT cells against colorectal cancer, and potentially, other solid tumours.
Vδ1+ γδT cells are a subset of lymphocytes that displays broad tumour reactivity. Critically, their activation is independent of tumour mutational load and of HLA/MHC-presentation, which enables their application in an allogeneic setting. Previously, our lab has developed a clinical-grade protocol to expand and differentiate peripheral blood Vδ1+ γδT cells leading to the generation of an immunotherapeutic product termed Delta One T (DOT) cells – which is currently in clinical trials against chemoresistant Acute Myeloid Leukaemia. We aim to repurpose DOT cells for solid tumours, in particular colon cancer. However, some hurdles imposed by the solid tumour microenvironment (TME) are expected to hamper DOT-cell efficacy. Here we propose to study the impact on DOT-cell function of two well-known TME roadblocks: two different nutrient deprivation. We also aim to find strategies to overcome the limitations imposed by these factors. We demonstrated that restriction of two nutrients dampened DOT-cell interferon-γ (IFN-γ) production, granzyme/perforin expression and decreased its antitumour killing capacity. Importantly, one nutrient impacted DOT cells more severely than the other. We then tested four different drugs to revert the impact of nutrient starvation on DOT cells. While most of them failed to revert the phenotype, we found one drug able to partially revert the effect of both nutrient restrictions by increasing IFN-γ expression. In conclusion, we demonstrate that nutrient availability in the TME decreases the antitumour capacity of DOT cells and we unravel a potential drug that can improve DOT-cell antitumour function. These discoveries will be critical for the design of new protocols to improve the efficacy of DOT cells against colorectal cancer, and potentially, other solid tumours.
Descrição
Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2022
Palavras-chave
Privação de nutrientes Microambiente tumoral Imunoterapia Células DOT