RESUMEN
The median overall survival for children with diffuse intrinsic pontine glioma (DIPG) is less than one year. The majority of diffuse midline gliomas, including more than 70% of DIPGs, harbor an amino acid substitution from lysine (K) to methionine (M) at position 27 of histone 3 variant 3 (H3.3). From a CD8+ T cell clone established by stimulation of HLA-A2+ CD8+ T cells with synthetic peptide encompassing the H3.3K27M mutation, complementary DNA for T cell receptor (TCR) α- and ß-chains were cloned into a retroviral vector. TCR-transduced HLA-A2+ T cells efficiently killed HLA-A2+H3.3K27M+ glioma cells in an antigen- and HLA-specific manner. Adoptive transfer of TCR-transduced T cells significantly suppressed the progression of glioma xenografts in mice. Alanine-scanning assays suggested the absence of known human proteins sharing the key amino acid residues required for recognition by the TCR, suggesting that the TCR could be safely used in patients. These data provide us with a strong basis for developing T cell-based therapy targeting this shared neoepitope.
Asunto(s)
Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Glioma/genética , Glioma/inmunología , Histonas/genética , Histonas/inmunología , Mutación , Linfocitos T/inmunología , Linfocitos T/metabolismo , Traslado Adoptivo , Secuencia de Aminoácidos , Aminoácidos , Animales , Presentación de Antígeno , Antígenos de Neoplasias/química , Cromatografía Liquida , Modelos Animales de Enfermedad , Mapeo Epitopo , Femenino , Glioma/patología , Glioma/terapia , Antígenos HLA-A/inmunología , Antígenos HLA-A/metabolismo , Histonas/química , Humanos , Inmunoterapia Adoptiva , Ratones , Ratones Transgénicos , Péptidos/química , Péptidos/inmunología , Péptidos/metabolismo , Unión Proteica , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Especificidad del Receptor de Antígeno de Linfocitos T/inmunología , Espectrometría de Masas en Tándem , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The high affinity leukotriene B4 receptor, BLT1 mediates chemotaxis of diverse leukocyte subsets to the sites of infection or inflammation. Whereas the pathological functions of LTB4/BLT1 axis in allergy, autoimmunity and cardiovascular disorders are well established; its role in cancer is only beginning to emerge. In this review, we summarize recent findings on LTB4/BLT1 axis enabling distinct outcomes toward tumor progression. In a mouse lung tumor model promoted by silicosis-induced inflammation, genetic deletion of BLT1 attenuated neutrophilic inflammation and tumor promotion. In contrast, in a spontaneous model of intestinal tumorigenesis, absence of BLT1 led to defective mucosal host response, altered microbiota and bacteria dependent colon tumor progression. Furthermore, BLT1 mediated CD8+ T cell recruitment was shown to be essential for initiating anti-tumor immunity in number of xenograft models and is critical for effective PD1 based immunotherapy. BLT2 mediated chemotherapy resistance, tumor promotion and metastasis are also discussed. This new information points to a paradigm shift in our understanding of the LTB4 pathways in cancer.