RESUMO
Antagonism of the PD-1/PD-L1 axis is a critical therapeutic strategy for patients with advanced bladder cancer. IFNγ functions as a key regulator of PD-L1 in both immune as well as cancer cells. Forkhead box P3 (FOXP3) is a transcription factor synonymous in T regulatory cell function but with increasingly described functions in cancer cells. Here, we investigated the relationship between FOXP3 and PD-L1 in bladder cancer. We showed that FOXP3 is critical in the ability for IFNγ to activate PD-L1 in bladder cancer cells. FOXP3 can bind to the PD-L1 promoter and induces a gene program that leads to regulation of multiple immune-related genes and genes involved in epithelial-to-mesenchymal transition (EMT). Using in vitro and in vivo human and murine models, we showed that FOXP3 can influence bladder cancer EMT as well as promote cancer metastases. Furthermore, FOXP3 may be a convergent factor for multiple activators of PD-L1, including the chemotherapeutic drug cisplatin. SIGNIFICANCE: Historically a key transcription factor driving T regulatory cell function, FOXP3 has an increasingly recognized role in cancer cells. In bladder cancer, we defined a novel mechanism whereby FOXP3 mediates the activation of the immune checkpoint PD-L1 by the cytokine IFNγ. We also showed that FOXP3 induces other immune checkpoints as well as genes involved in EMT, promoting immune resistance and cancer metastases.
Assuntos
Antígeno B7-H1 , Transição Epitelial-Mesenquimal , Fatores de Transcrição Forkhead , Interferon gama , Neoplasias da Bexiga Urinária , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/metabolismo , Transição Epitelial-Mesenquimal/genética , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Humanos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Animais , Interferon gama/metabolismo , Interferon gama/genética , Camundongos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , FemininoRESUMO
After heart injury, dead heart muscle is replaced by scar tissue. Fibroblasts can electrically couple with myocytes, and changes in fibroblast membrane potential can lead to myocyte excitability, which suggests that fibroblast-myocyte coupling in scar tissue may be responsible for arrhythmogenesis. However, the physiologic relevance of electrical coupling of myocytes and fibroblasts and its impact on cardiac excitability in vivo have never been demonstrated. We genetically engineered a mouse that expresses the optogenetic cationic channel ChR2 (H134R) exclusively in cardiac fibroblasts. After myocardial infarction, optical stimulation of scar tissue elicited organ-wide cardiac excitation and induced arrhythmias in these animals. Complementing computational modeling with experimental approaches, we showed that gap junctional and ephaptic coupling, in a synergistic yet functionally redundant manner, excited myocytes coupled to fibroblasts.
Assuntos
Arritmias Cardíacas , Channelrhodopsins , Cicatriz , Fibroblastos , Miócitos Cardíacos , Animais , Camundongos , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Cicatriz/patologia , Cicatriz/fisiopatologia , Fibroblastos/fisiologia , Miócitos Cardíacos/fisiologia , Channelrhodopsins/genética , Channelrhodopsins/fisiologia , Optogenética , Conexina 43/genética , Conexina 43/fisiologia , Técnicas de Inativação de GenesRESUMO
Myelodysplastic syndromes (MDS) are a group of incurable hematopoietic stem cell (HSC) neoplasms characterized by peripheral blood cytopenias and a high risk of progression to acute myeloid leukemia. MDS represent the final stage in a continuum of HSCs' genetic and functional alterations and are preceded by a premalignant phase, clonal cytopenia of undetermined significance (CCUS). Dissecting the mechanisms of CCUS maintenance may uncover therapeutic targets to delay or prevent malignant transformation. Here, we demonstrate that DNMT3A and TET2 mutations, the most frequent mutations in CCUS, induce aberrant HSCs' differentiation towards the myeloid lineage at the expense of erythropoiesis by upregulating IL-1ß-mediated inflammatory signaling and that canakinumab rescues red blood cell transfusion dependence in early-stage MDS patients with driver mutations in DNMT3A and TET2 . This study illuminates the biological landscape of CCUS and offers an unprecedented opportunity for MDS intervention during its initial phase, when expected survival is prolonged.