Facultad de Farmacia
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Browsing Facultad de Farmacia by Author "Antilef Cáceres, Bárbara Evelyn"
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Item Efecto de la transferencia artificial de mitocondrias obtenidas desde línea celular hsc-3 sobre el fenotipo y metabolismo de linfocitos t cd4+.(Universidad de Concepción., 2023) Antilef Cáceres, Bárbara Evelyn; Nova Lamperti, Estefanía Andrea; Pérez de Armas, Andy J.Oral squamous cell carcinoma (OSCC) is the most frequent type of oral cancer in Chile and the world. Has been reported that the OSCC tumour microenvironment (TME) induces impaired T cell responses, promoting an exhausted phenotype and metabolic reprogramming. The mitochondria is the main metabolic organelle and in recent years it has been shown that several cells have the capacity to transfer mitochondria, including cancer cells. However, to date, it has not been evaluated whether mitochondrias transfer from cancer cells to T lymphocytes promotes an exhausted phenotype in T helper cells. The aim of this work was to analyse the exhausted phenotype with metabolic changes in TCD4+ lymphocytes after artificial transfer of mitochondria (MitoCeption) obtained from the oral cancer cell line HSC-3. The methodology was based on the standardization of artificial mitochondrial transfer using isolated mitochondria and labelled with MitoTrackerGreen from oral cáncer cells to CD4+ T lymphocytes through MitoCeption. Then, surface molecule expression, proliferation and cytokine secretion mediated by tumor mitochondrial transfer were analyzed by flow cytometry in order to analysed the exhausted phenotype. Also, it was analysed the metabolome, the production of superoxide and glucose metabolism such as the catchment and consumption of glucose and concentration of lactate. The results showed that TCD4+ lymphocytes that acquired mitochondria had increased expression of 2 inhibitory proteins (TIGIT and CTLA4) and 3 proteins associated with exhausted phenotype (PD-1, PLD-1 and LAG3), compared to the control group. In addition, the mitocepted lymphocytes exhibited a significant decrease in proliferation compared to the control, non-mitocepted cells. For cytokine analysis, a significant decrease was observed in the mitocepted group in the secretion of IFN-gamma, TNF-alpha, IL-10, and IL-4, TH1 and TH2 pathway cytokines compared to control. Metabolomic analysis showed a reduction in the pyruvate dehydrogenase cofactor called Vitamin B1 or thiamine and an increase in mitochondrial superoxide production in the mitocepted group versus the control. Also, its observed a high catchment and consumption of glucose in mitocepted CD4+ lymphocyte with tumoral mitochondria, in addition of a higher concentration of lactate in supernatant of this cells unlike the control. Therefore, the acquisition of isolated mitochondria from HSC-3 cancer cells by CD4+ T lymphocyte induces mitochondrial oxidative stress in the recipient cell and a possible reduction of the Krebs cycle, mediated by low thiamine. This effect promotes a salvage glycolytic metabolism and a change in lymphocyte functionality, promoting an exhausted phenotype and a dysfunctional TCD4+ cell, thus affecting the anti-tumor response.