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

Manav Korpal (), Xiaoling Puyang, Zhenhua Jeremy Wu, Roland Seiler, Craig Furman, Htoo Zarni 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 and Ping Zhu ()
Additional contact information
Manav Korpal: H3 Biomedicine Inc.
Xiaoling Puyang: H3 Biomedicine Inc.
Zhenhua Jeremy Wu: H3 Biomedicine Inc.
Roland Seiler: University of British Columbia
Craig Furman: H3 Biomedicine Inc.
Htoo Zarni Oo: University of British Columbia
Michael Seiler: H3 Biomedicine Inc.
Sean Irwin: H3 Biomedicine Inc.
Vanitha Subramanian: H3 Biomedicine Inc.
Jaya Julie Joshi: H3 Biomedicine Inc.
Chris K. Wang: University of British Columbia
Victoria Rimkunas: H3 Biomedicine Inc.
Davide Tortora: University of British Columbia
Hua Yang: Eisai Inc., 4 Corporate Drive
Namita Kumar: Eisai Inc., 4 Corporate Drive
Galina Kuznetsov: Eisai Inc., 4 Corporate Drive
Mark Matijevic: Eisai Inc., 4 Corporate Drive
Jesse Chow: Eisai Inc., 4 Corporate Drive
Pavan Kumar: H3 Biomedicine Inc.
Jian Zou: H3 Biomedicine Inc.
Jacob Feala: H3 Biomedicine Inc.
Laura Corson: H3 Biomedicine Inc.
Ryan Henry: H3 Biomedicine Inc.
Anand Selvaraj: H3 Biomedicine Inc.
Allison Davis: H3 Biomedicine Inc.
Kristjan Bloudoff: H3 Biomedicine Inc.
James Douglas: University Hospital of Southampton
Bernhard Kiss: University of Bern
Morgan Roberts: University of British Columbia
Ladan Fazli: University of British Columbia
Peter C. Black: University of British Columbia
Peter Fekkes: H3 Biomedicine Inc.
Peter G. Smith: H3 Biomedicine Inc.
Markus Warmuth: H3 Biomedicine Inc.
Lihua Yu: H3 Biomedicine Inc.
Ming-Hong Hao: H3 Biomedicine Inc.
Nicholas Larsen: H3 Biomedicine Inc.
Mads Daugaard: University of British Columbia
Ping Zhu: H3 Biomedicine Inc.

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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 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.

Date: 2017
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DOI: 10.1038/s41467-017-00147-w

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