RESUMO
Unleashing antitumor T cell activity by checkpoint inhibitor immunotherapy is effective in cancer patients, but clinical responses are limited. Cytokine signaling through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway correlates with checkpoint immunotherapy resistance. We report a phase I clinical trial of the JAK inhibitor ruxolitinib with anti-PD-1 antibody nivolumab in Hodgkin lymphoma patients relapsed or refractory following checkpoint inhibitor immunotherapy. The combination yielded a best overall response rate of 53% (10/19). Ruxolitinib significantly reduced neutrophil-to-lymphocyte ratios and percentages of myeloid suppressor cells but increased numbers of cytokine-producing T cells. Ruxolitinib rescued the function of exhausted T cells and enhanced the efficacy of immune checkpoint blockade in preclinical solid tumor and lymphoma models. This synergy was characterized by a switch from suppressive to immunostimulatory myeloid cells, which enhanced T cell division.
Assuntos
Doença de Hodgkin , Inibidores de Checkpoint Imunológico , Inibidores de Janus Quinases , Nitrilas , Nivolumabe , Pirazóis , Pirimidinas , Linfócitos T , Adulto , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sinergismo Farmacológico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/imunologia , Doença de Hodgkin/terapia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/metabolismo , Janus Quinases/antagonistas & inibidores , Nitrilas/uso terapêutico , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Linfócitos T/imunologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos BALB CRESUMO
Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. Together, these findings underscore TERT's critical role in aging processes and provide preclinical proof of concept for physiological TERT activation as a strategy to mitigate multiple aging hallmarks and associated pathologies.
Assuntos
Envelhecimento , Metilação de DNA , Telomerase , Telomerase/metabolismo , Telomerase/genética , Humanos , Animais , Camundongos , DNA (Citosina-5-)-Metiltransferases/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , Senescência Celular , Regiões Promotoras Genéticas , DNA Metiltransferase 3B , Encéfalo/metabolismo , Telômero/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Fator de Transcrição AP-1/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , NeurogêneseRESUMO
Phospholipase D3 (PLD3) and D4 (PLD4) are endolysosomal exonucleases of ssDNA and ssRNA that regulate innate immunity. Polymorphisms of these enzymes are correlated with numerous human diseases, including Alzheimer's, rheumatoid arthritis, and systemic sclerosis. Pharmacological modulation of these immunoregulatory proteins may yield novel immunotherapies and adjuvants. A previous study reported a high-throughput screen (N = 17,952) that discovered a PLD3-selective activator and inhibitor, as well as a nonselective inhibitor, but failed to identify selective modulators of PLD4. However, modulators selective for PLD4 are therapeutically pertinent, since recent reports have shown that regulating this protein has direct implications in cancer and autoimmune diseases. Furthermore, the high expression of PLD4 in dendritic and myeloid cells, in comparison to the broader expression of PLD3, presents the opportunity for a cell-targeted immunotherapy. Here, we describe screening of an expended diversity library (N = 45,760) with an improved platform and report the discovery of one inhibitor and three activators selective for PLD4. Furthermore, kinetic modeling and structural analysis suggest mechanistic differences in the modulation of these hits. These findings further establish the utility of this screening platform and provide a set of chemical scaffolds to guide future small-molecule development for this novel immunoregulator target.