RESUMO
Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. Although immunotherapies are approved for MIBC, the majority of patients fail to respond, suggesting existence of complementary immune evasion mechanisms. Here, we report that the PPARγ/RXRα pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC. Recurrent mutations in RXRα at serine 427 (S427F/Y), through conformational activation of the PPARγ/RXRα heterodimer, and focal amplification/overexpression of PPARγ converge to modulate PPARγ/RXRα-dependent transcription programs. Immune cell-infiltration is controlled by activated PPARγ/RXRα that inhibits expression/secretion of inflammatory cytokines. Clinical data sets and an in vivo tumor model indicate that PPARγHigh/RXRαS427F/Y impairs CD8+ T-cell infiltration and confers partial resistance to immunotherapies. Knockdown of PPARγ or RXRα and pharmacological inhibition of PPARγ significantly increase cytokine expression suggesting therapeutic approaches to reviving immunosurveillance and sensitivity to immunotherapies. Our study reveals a class of tumor cell-intrinsic "immuno-oncogenes" that modulate the immune microenvironment of cancer.Muscle-invasive bladder cancer (MIBC) is a potentially lethal disease. Here the authors characterize diverse genetic alterations in MIBC that convergently lead to constitutive activation of PPARgamma/RXRalpha and result in immunosurveillance escape by inhibiting CD8+ T-cell recruitment.
Assuntos
Evasão da Resposta Imune/imunologia , Monitorização Imunológica , PPAR gama/imunologia , Receptor X Retinoide alfa/imunologia , Neoplasias da Bexiga Urinária/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Perfilação da Expressão Gênica/métodos , Células HCT116 , Humanos , Immunoblotting , Imunoterapia/métodos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Camundongos , Microscopia de Fluorescência , Mutação/imunologia , Invasividade Neoplásica , PPAR gama/química , PPAR gama/genética , Multimerização Proteica/imunologia , Receptor X Retinoide alfa/química , Receptor X Retinoide alfa/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/terapiaRESUMO
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Assuntos
Humanos , Masculino , Feminino , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/imunologia , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Mutação/imunologia , Mutação/fisiologia , NADPH Oxidases/imunologia , NADPH Oxidases/uso terapêutico , Burkholderia cepacia/patogenicidade , Staphylococcus aureus/patogenicidade , Salmonella/patogenicidade , Serratia marcescens/patogenicidade , Nocardia/patogenicidade , Aspergillus/patogenicidade , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/patologia , Rifampina/uso terapêutico , Isoniazida/uso terapêutico , Clotrimazol/uso terapêutico , Tuberculose/imunologia , Tuberculose/patologiaRESUMO
Competition for iron influences host-pathogen interactions. Pathogens secrete small iron-binding moieties, siderophores, to acquire host iron. In response, the host secretes siderophore-binding proteins, such as lipocalin 24p3, which limit siderophore-mediated iron import into bacteria. Mammals produce 2,5-dihydroxy benzoic acid, a compound that resembles a bacterial siderophore. Our data suggest that bacteria use both mammalian and bacterial siderophores. In support of this idea, supplementation with mammalian siderophore enhances bacterial growth in vitro. In addition, mice lacking the mammalian siderophore resist E. coli infection. Finally, we show that the host responds to infection by suppressing siderophore synthesis while up-regulating lipocalin 24p3 expression via TLR signaling. Thus, reciprocal regulation of 24p3 and mammalian siderophore is a protective mechanism limiting microbial access to iron.
Assuntos
Infecções Bacterianas/imunologia , Gentisatos/imunologia , Hidroxibutirato Desidrogenase/imunologia , Imunidade Inata/imunologia , Sideróforos/imunologia , Proteínas de Fase Aguda/genética , Proteínas de Fase Aguda/imunologia , Proteínas de Fase Aguda/metabolismo , Animais , Infecções Bacterianas/genética , Infecções Bacterianas/metabolismo , Proteínas da Membrana Bacteriana Externa/genética , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Candida albicans/imunologia , Candida albicans/fisiologia , Candidíase/genética , Candidíase/imunologia , Candidíase/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismo , Linhagem Celular , Enterobactina/imunologia , Enterobactina/metabolismo , Escherichia coli/genética , Escherichia coli/imunologia , Escherichia coli/fisiologia , Feminino , Gentisatos/metabolismo , Hidroxibutirato Desidrogenase/genética , Hidroxibutirato Desidrogenase/metabolismo , Imunidade Inata/genética , Immunoblotting , Estimativa de Kaplan-Meier , Lipocalina-2 , Lipocalinas/genética , Lipocalinas/imunologia , Lipocalinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/imunologia , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/imunologia , Proteínas Oncogênicas/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo , Interferência de RNA , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sideróforos/metabolismo , Staphylococcus aureus/imunologiaRESUMO
The cloning of the PIG-A gene has facilitated the unraveling of the complex pathophysiology of paroxysmal nocturnal hemoglobinuria (PNH). Of current major concern is the mechanism by which a PNH clone expands. Many reports have suggested that an immune mechanism operates to cause bone marrow failure in some patients with PNH, aplastic anemia, and myelodysplastic syndromes. Because blood cells of PNH phenotype are often found in patients with these marrow diseases, one hypothesis is that the PNH clone escapes immune attack, producing a survival advantage by immunoselection. To test this hypothesis, we examined the sensitivity of blood cells, with or without PIG-A mutations, to killing by natural killer (NK) cells, using 51Cr-release assay in vitro. To both peripheral blood and cultured NK cells, PIG-A mutant cells prepared from myeloid and lymphoid leukemic cell lines were less susceptible than their control counterparts (reverted from the mutant cells by transfection with a PIG-A cDNA). NK activity was completely abolished with concanamycin A and by calcium chelation, indicating that killing was perforin-dependent. There were no differences in major histocompatibility (MHC) class I expression or sensitivity to either purified perforin or to interleukin-2-activated NK cells between PIG-A mutant and control cells. From these results, we infer that PIG-A mutant cells lack molecules needed for NK activation or to trigger perforin-mediated killing. Our experiments suggest that PIG-A mutations confer a relative survival advantage to a PNH clone, contributing to selective expansion of these cells in the setting of marrow injury by cytotoxic lymphocytes.