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Evasion of immunosurveillance by genomic alterations of PPAR?/RXR? in bladder cancer.

ABSTRACT: 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 PPAR?/RXR? pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC. Recurrent mutations in RXR? at serine 427 (S427F/Y), through conformational activation of the PPAR?/RXR? heterodimer, and focal amplification/overexpression of PPAR? converge to modulate PPAR?/RXR?-dependent transcription programs. Immune cell-infiltration is controlled by activated PPAR?/RXR? that inhibits expression/secretion of inflammatory cytokines. Clinical data sets and an in vivo tumor model indicate that PPAR?High/RXR?S427F/Y impairs CD8+ T-cell infiltration and confers partial resistance to immunotherapies. Knockdown of PPAR? or RXR? and pharmacological inhibition of PPAR? 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.

SUBMITTER: Korpal M

PROVIDER: S-EPMC5524640 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer.

Korpal Manav M Puyang Xiaoling X Jeremy Wu Zhenhua Z Seiler Roland R Furman Craig C Oo Htoo Zarni HZ Seiler Michael M Irwin Sean S Subramanian Vanitha V Julie Joshi Jaya J Wang Chris K CK Rimkunas Victoria V Tortora Davide D Yang Hua H Kumar Namita N Kuznetsov Galina G Matijevic Mark M Chow Jesse J Kumar Pavan P Zou Jian J Feala Jacob J Corson Laura L Henry Ryan R Selvaraj Anand A Davis Allison A Bloudoff Kristjan K Douglas James J Kiss Bernhard B Roberts Morgan M Fazli Ladan L Black Peter C PC Fekkes Peter P Smith Peter G PG Warmuth Markus M Yu Lihua L Hao Ming-Hong MH Larsen Nicholas N Daugaard Mads M Zhu Ping P

Nature communications 20170724 1

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 a ...[more]

PMID: 28740126

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Project description:Organotins are a group of chemical compounds that have a tin atom covalently bound to one or more organic groups. The best-studied organotin is tributyltin chloride, which is an environmental pollutant and an endocrine disruptor. Tributyltin chloride has been shown to bind to PPARγ/RXRα and induces adipogenesis in different mammalian cells. However, there are few studies with other organotin compounds, such as dibutyltins. The aim of this study was to investigate the effect of dibutyltins diacetate, dichloride, dilaurate, and maleate on the transcriptional activity of the nuclear PPARγ and RXRα receptors, and on adipogenesis and inflammation. Analogous to tributyltin chloride, in reporter gene assay using HeLa cells, we observed that dibutyltins diacetate, dichloride, dilaurate, and maleate are partial agonists of PPARγ. Unlike tributyltin chloride, which is a full agonist of RXRα, dibutyltins dichloride and dilaurate are partial RXRα agonists. Additionally, the introduction of the C285S mutation, which disrupts tributyltin chloride binding to PPARγ, abrogated the dibutyltin agonistic activity. In 3T3-L1 preadipocytes, all dibutyltin induced adipogenesis, although the effect was less pronounced than that of rosiglitazone and tributyltin chloride. This adipogenic effect was confirmed by the expression of adipogenic markers Fabp4, Adipoq, and Glut4. Exposure of 3T3-L1 cells with dibutyltin in the presence of T0070907, a specific PPARγ antagonist, reduced fat accumulation, suggesting that adipogenic effect occurs through PPARγ. Furthermore, dibutyltins dichloride, dilaurate, and maleate inhibited the expression of proinflammatory genes in 3T3-L1 cells, such as Vcam1, Dcn, Fn1, S100a8, and Lgals9. Additionally, in RAW 264.7 macrophages, tributyltin chloride and dibutyltin dilaurate reduced LPS-stimulated TNFα expression. Our findings indicate that dibutyltins diacetate, dichloride, dilaurate, and maleate are PPARγ partial agonists and that dibutyltins dichloride and dilaurate are also partial RXRα agonists. Furthermore, dibutyltins induce adipogenesis in a PPARγ-dependent manner and repress inflammatory genes in 3T3-L1 and RAW 264.7 cells. Although dibutyltins display some partial PPARγ/RXRα agonistic effects, the translation of cell-based results assays into in vivo effects on inflammation and insulin resistance is not entirely known. Nevertheless, further studies are necessary to address their effects in different periods of life and to elucidate the actions of organostanic compounds in whole-body context.

Dataset Information

Evasion of immunosurveillance by genomic alterations of PPAR?/RXR? in bladder cancer.

Publications

Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer.

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