RESUMEN
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease affecting the central nervous system in young adults. Heparan sulfate proteoglycans (HSPGs) are ubiquitous to the cell surface and the extracellular matrix. HSPG biosynthesis is a complex process involving enzymatic attachment of heparan sulfate (HS) chains to a core protein. HS side chains mediate specific ligand and growth factor interactions directing cellular processes including cell adhesion, migration and differentiation. Two main families of HSPGs exist, the syndecans (SDC1-4) and glypicans (GPC1-6). The SDCs are transmembrane proteins, while the GPC family are GPI linked to the cell surface. SDC1 has well-documented interactions with numerous signalling pathways. Genome-wide association studies (GWAS) have identified regions of the genome associated with MS including a region on chromosome 13 containing GPC5 and GPC6. International studies have revealed significant associations between this region and disease development. The exostosin-1 (EXT1) and sulfatase-1 (SULF1) are key enzymes contributing to the generation of HS chains. EXT1, with documented tumour suppressor properties, is involved in the initiation and polymerisation of the growing HS chain. SULF1 removes 6-O-sulfate groups from HS chains, affecting protein-ligand interactions and subsequent downstream signalling with HS modification potentially having significant effects on MS progression. In this study, we identified significant associations between single nucleotide polymorphisms in SDC1, GPC5 and GPC6 and MS in an Australian Caucasian case-control population. Further significant associations in these genes were identified when the population was stratified by sex and disease subtype. No association was found for EXT1 or SULF1.
Asunto(s)
Biomarcadores/análisis , Estudio de Asociación del Genoma Completo , Proteoglicanos de Heparán Sulfato/química , Esclerosis Múltiple/patología , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Estudios de Casos y Controles , Femenino , Glipicanos/genética , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/enzimología , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/genética , N-Acetilglucosaminiltransferasas/genética , Sulfotransferasas/genética , Sindecano-1/genética , Adulto JovenRESUMEN
Autologous T cells genetically modified with a chimeric antigen receptor (CAR) redirected at CD19 have potent activity in the treatment of B cell leukemia and B cell non-Hodgkin's lymphoma (B-NHL). Immunotherapies to treat multiple myeloma (MM) targeted the B cell maturation antigen (BCMA), which is expressed in most cases of MM. We developed a humanized CAR with specificity for BCMA based on our previously generated anti-BCMA monoclonal antibody. The targeting single-chain variable fragment (scFv) domain exhibited a binding affinity in the low nanomolar range, conferring T cells with high functional avidity. Redirecting T cells by this CAR allowed us to explore BCMA as an alternative target for mature B-NHLs. We validated BCMA expression in diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia. BCMA CAR T cells triggered target cell lysis with an activation threshold in the range of 100 BCMA molecules, which allowed for an efficient eradication of B-NHL cells in vitro and in vivo. Our data corroborate BCMA is a suitable target in B cell tumors beyond MM, providing a novel therapeutic option for patients where BCMA is expressed at low abundance or where anti-CD19 immunotherapies have failed due to antigen loss.
Asunto(s)
Antígeno de Maduración de Linfocitos B/inmunología , Linfoma de Células B/terapia , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/trasplante , Animales , Línea Celular Tumoral , Humanos , Inmunoterapia Adoptiva , Células Jurkat , Linfoma de Células B/inmunología , Ratones , Receptores Quiméricos de Antígenos/genética , Linfocitos T/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Deletion 1p36 syndrome is recognized as the most common terminal deletion syndrome. Here, we describe the loss of a gene within the deletion that is responsible for the cardiomyopathy associated with monosomy 1p36, and we confirm its role in nonsyndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). With our own data and publically available data from array comparative genomic hybridization (aCGH), we identified a minimal deletion for the cardiomyopathy associated with 1p36del syndrome that included only the terminal 14 exons of the transcription factor PRDM16 (PR domain containing 16), a gene that had previously been shown to direct brown fat determination and differentiation. Resequencing of PRDM16 in a cohort of 75 nonsyndromic individuals with LVNC detected three mutations, including one truncation mutant, one frameshift null mutation, and a single missense mutant. In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported nonsynonymous variants in the coding region of PRDM16. None of the PRDM16 mutations identified were observed in more than 6,400 controls. PRDM16 has not previously been associated with cardiac disease but is localized in the nuclei of cardiomyocytes throughout murine and human development and in the adult heart. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in both contractile dysfunction and partial uncoupling of cardiomyocytes and also revealed evidence of impaired cardiomyocyte proliferative capacity. In conclusion, mutation of PRDM16 causes the cardiomyopathy in 1p36 deletion syndrome as well as a proportion of nonsyndromic LVNC and DCM.
Asunto(s)
Cardiomiopatía Dilatada/genética , Trastornos de los Cromosomas/genética , Mapeo Cromosómico/métodos , Proteínas de Unión al ADN/genética , No Compactación Aislada del Miocardio Ventricular/genética , Factores de Transcripción/genética , Animales , Cardiomiopatía Dilatada/patología , Estudios de Casos y Controles , Proliferación Celular , Deleción Cromosómica , Cromosomas Humanos Par 1/genética , Hibridación Genómica Comparativa , Exones , Mutación del Sistema de Lectura , Humanos , Mutación Missense , Contracción Miocárdica , Miocitos Cardíacos , Pez Cebra/embriología , Pez Cebra/genéticaRESUMEN
The focus in cancer immunotherapy has mainly been on CD8 T cells, as they can directly recognize cancer cells. CD4 T cells have largely been neglected, because most cancers lack MHC II expression and cannot directly be recognized by CD4 T cells. Yet, tumor antigens can be captured and cross-presented by MHC II-expressing tumor stromal cells. Recent data suggest that CD4 T cells act as a swiss army knife against tumors. They can kill cancer cells, if they express MHC II, induce tumoricidal macrophages, induces cellular senescence of cancer cells, destroy the tumor vasculature through cytokine release and help CD8 T cells in the effector phase. We foresee a great future for CD4 T cells in the clinic, grafted with tumor antigen specificity by T cell receptor gene transfer, either alone or in combination with engineered CD8 T cells.
Asunto(s)
Linfocitos T CD4-Positivos , Neoplasias , Antígenos de Neoplasias , Linfocitos T CD8-positivos , Antígenos de Histocompatibilidad Clase II , Humanos , Inmunoterapia , Neoplasias/terapiaRESUMEN
CAR-T cell therapy targeting CD19 demonstrated strong activity against advanced B cell leukemia, however shows less efficacy against lymphoma with nodal dissemination. To target both B cell Non-Hodgkin's lymphoma (B-NHLs) and follicular T helper (Tfh) cells in the tumor microenvironment (TME), we apply here a chimeric antigen receptor (CAR) that recognizes human CXCR5 with high avidity. CXCR5, physiologically expressed on mature B and Tfh cells, is also highly expressed on nodal B-NHLs. Anti-CXCR5 CAR-T cells eradicate B-NHL cells and lymphoma-supportive Tfh cells more potently than CD19 CAR-T cells in vitro, and they efficiently inhibit lymphoma growth in a murine xenograft model. Administration of anti-murine CXCR5 CAR-T cells in syngeneic mice specifically depletes endogenous and malignant B and Tfh cells without unexpected on-target/off-tumor effects. Collectively, anti-CXCR5 CAR-T cells provide a promising treatment strategy for nodal B-NHLs through the simultaneous elimination of lymphoma B cells and Tfh cells of the tumor-supporting TME.