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

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 PPARγ(High)/RXRα(S427F/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.

Nature communications. 2017 Jul 24*** epublish ***

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

H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA, 02139, USA. ., H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA, 02139, USA., Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada, V5Z 1M9., Eisai Inc., 4 Corporate Drive, Andover, MA, 01810, USA., Department of Urology, University Hospital of Southampton, Hampshire, SO16 6YD, UK., Department of Urology, University of Bern, Bern, CH-3010, Switzerland., H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA, 02139, USA. .

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