RESUMO
Regulatory T cell (Treg) therapy is a potential curative approach for a variety of immune-mediated conditions, including autoimmunity and transplantation, in which there is pathological tissue damage. In mice, IL-33R (ST2)-expressing Tregs mediate tissue repair by producing the growth factor amphiregulin, but whether similar tissue-reparative Tregs exist in humans remains unclear. We show that human Tregs in blood and multiple tissue types produced amphiregulin, but this was neither a unique feature of Tregs nor selectively upregulated in tissues. Human Tregs in blood, tonsil, synovial fluid, colon, and lung tissues did not express ST2, so ST2+ Tregs were engineered via lentiviral-mediated overexpression, and their therapeutic potential for cell therapy was examined. Engineered ST2+ Tregs exhibited TCR-independent, IL-33-stimulated amphiregulin expression and a heightened ability to induce M2-like macrophages. The finding that amphiregulin-producing Tregs have a noneffector phenotype and are progressively lost upon TCR-induced proliferation and differentiation suggests that the tissue repair capacity of human Tregs may be an innate function that operates independently from their classical suppressive function.
Assuntos
Proliferação de Células , Imunidade Inata/fisiologia , Linfócitos T Reguladores/imunologia , Adulto , Feminino , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-33 , Macrófagos/citologia , Macrófagos/imunologia , Masculino , Especificidade de Órgãos , Linfócitos T Reguladores/citologiaRESUMO
The Notch ligand, JAG1 is associated with breast cancer recurrence. Herein, we report on a genomics approach to elucidate mechanisms downstream of JAG1 that promote breast cancer growth. In a survey of 46 breast cancer cell lines, we found that triple negative (TN; basal and mesenchymal ER-, PR-, and Her2-negative) lines express JAG1 at significantly higher levels than do HER2(+) or luminal (ER(+)) Her2(-) cell lines. In contrast to the luminal lines tested (T47D and MCF7), TN breast cancer cell lines (HCC1143 and MDA MB231) display high-level JAG1 expression and growth inhibition with RNA interference-induced JAG1 down-regulation. We used microarray profiling of TN tumor cells transfected with JAG1 siRNA to identify JAG1-regulated genes (P
Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Ciclina D1/metabolismo , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/genética , Western Blotting , Neoplasias da Mama/genética , Proteínas de Ligação ao Cálcio/genética , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Ciclina D1/genética , Feminino , Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteína Jagged-1 , Proteínas de Membrana/genética , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas/genética , RNA Interferente Pequeno , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Receptores de Estrogênio/biossíntese , Receptores de Estrogênio/genética , Receptores Notch/genética , Receptores de Progesterona/biossíntese , Receptores de Progesterona/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Serrate-Jagged , TransfecçãoRESUMO
As a result of a spectrum of mitochondrial defects, tumor cells often preferentially use glycolysis to generate adenosine triphosphate (ATP), even in the presence of oxygen, a phenomenon known as aerobic glycolysis, or the "Warburg effect." Dichloroacetate (DCA) is an inhibitor of mitochondrial pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), a gatekeeping enzyme for the entry of pyruvate into the mitochondrial tricarboxylic acid (TCA) cycle. In mice, DCA treatment appears to reactivate mitochondrial respiration in tumor cells, induces their selective killing, and suppresses cancer growth. These observations provide intriguing insights into the plasticity of tumor metabolism that may offer new opportunities for therapeutic intervention.