RESUMEN
Glioblastoma multiforme (GBM) is the most predominant and malignant primary brain tumor in adults. Thymic stromal lymphopoietin (TSLP), a cytokine primarily generated by activated epithelial cells, has recently garnered attention in cancer research. This study was aimed to elucidate the significance of TSLP in GBM cells and its interplay with the immune system, particularly focused on granulocyte neutrophils. Our results demonstrate that the tumor produces TSLP when stimulated with epidermal growth factor (EGF) in both the U251 cell line and the GBM biopsy (GBM-b). The relevance of the TSLP function was evaluated using a 3D spheroid model. Spheroids exhibited increased diameter, volume, and proliferation. In addition, TSLP promoted the generation of satellites surrounding the main spheroids and inhibited apoptosis in U251 treated with temozolomide (TMZ). Additionally, the co-culture of polymorphonuclear (PMN) cells from healthy donors with the U251 cell line in the presence of TSLP showed a reduction in apoptosis and an increase in IL-8 production. TSLP directly inhibited apoptosis in PMN from GBM patients (PMN-p). Interestingly, the vascular endothelial growth factor (VEGF) production was elevated in PMN-p compared with PMN from healthy donors. Under these conditions, TSLP also increased VEGF production, in PMN from healthy donors. Moreover, TSLP upregulated programed death-ligand 1 (PDL-1) expression in PMN cultured with U251. On the other hand, according to our results, the analysis of RNA-seq datasets from Illumina HiSeq 2000 sequencing platform performed with TIMER2.0 webserver demonstrated that the combination of TSLP with neutrophils decreases the survival of the patient. In conclusion, our results position TSLP as a possible new growth factor in GBM and indicate its modulation of the tumor microenvironment, particularly through its interaction with PMN.
Asunto(s)
Glioblastoma , Linfopoyetina del Estroma Tímico , Adulto , Humanos , Células Cultivadas , Citocinas/metabolismo , Neutrófilos/metabolismo , Microambiente Tumoral , Factor A de Crecimiento Endotelial VascularRESUMEN
PURPOSE: γδ T lymphocytes are non-conventional T cells that participate in protective immunity and tumor surveillance. In healthy humans, the main subset of circulating γδ T cells express the TCRVγ9Vδ2. This subset responds to non-peptide prenyl-pyrophosphate antigens such as (E)-4-hydroxy-3-methyl-but-enyl pyrophosphate (HMBPP). This unique feature of Vγ9Vδ2 T cells makes them a candidate for anti-tumor immunotherapy. In this study, we investigated the response of HMBPP-activated Vγ9Vδ2 T lymphocytes to glioblastoma multiforme (GBM) cells. METHODS: Human purified γδ T cells were stimulated with HMBPP (1 µM) and incubated with GBM cells (U251, U373 and primary GBM cultures) or their conditioned medium. After overnight incubation, expression of CD69 and perforin was evaluated by flow cytometry and cytokines production by ELISA. As well, we performed a meta-analysis of transcriptomic data obtained from The Cancer Genome Atlas. RESULTS: HMBPP-stimulated γδ T cells cultured with GBM or its conditioned medium increased CD69, intracellular perforin, IFN-γ, and TNF-α production. A meta-analysis of transcriptomic data showed that GBM patients display better overall survival when mRNA TRGV9, the Vγ9 chain-encoding gene, was expressed in high levels. Moreover, its expression was higher in low-grade GBM compared to GBM. Interestingly, there was an association between γδ T cell infiltrates and TNF-α expression in the tumor microenvironment. CONCLUSION: GBM cells enhanced Th1-like profile differentiation in phosphoantigen-stimulated γδ T cells. Our results reinforce data that have demonstrated the implication of Vγ9Vδ2 T cells in the control of GBM, and this knowledge is fundamental to the development of immunotherapeutic protocols to treat GBM based on γδ T cells.
Asunto(s)
Glioblastoma , Medios de Cultivo Condicionados , Difosfatos , Humanos , Activación de Linfocitos , Perforina , Receptores de Antígenos de Linfocitos T gamma-delta , Células TH1 , Microambiente Tumoral , Factor de Necrosis Tumoral alfaRESUMEN
El tratamiento quirurgico de las vias biliares, sera tema de comunicación científica constante tanto en congresos, revistas, simposiums, etc, de acuerdo con la aparición de nuevos procedimientos. Actualmente somos testigos y protagonistas de acontecimientos que estan ocurriendo en los ultimos 10 años y que estan cambiando los conceptos clásicos del tratamiento quirurgico de patologías del aparato digestivo. Es en merito de estos cambios que comunicamos nuestras primeras experiencias de 157 casos de Cirugía Laparoscópica realizadas en nuestro servicio y de estos, 153 fueron colecistectomia, una esplenectomia, una cirugia de hernia de Morgagni, una Vagotomia Troncular Bilateral Supra-diafragmática por toracoscopia y otra exploración y biopsia de tumor hepático. Asimismo, en uno de nuestros pacientes el estudio ecográfico preoperatorio reveló, la presencia de polipo vesicular cuyo estudio anatomopatológico determinó un adenocarcinoma in situ. queremos expresar también que ademas de la minima acción traumática que sufre el paciente en relación con la cirugia convencional, ha sido sorprendente la recuperación rapida de los pacientes y sureincorporación a sus centros de trabajo debido, fundamentalmente, a la baja morbilidad que ocasiona este procedimiento. Estamos convencidos que estan abiertas las puertas de una nueva era en la cirugía contemporanea