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

被引：104

作者：

Korpal, Manav ^{[1
]}

Puyang, Xiaoling ^{[1
]}

Wu, Zhenhua Jeremy ^{[1
]}

Seiler, Roland ^{[2
,3
]}

Furman, Craig ^{[1
]}

Oo, Htoo Z. ^{[2
,3
]}

Seiler, Michael ^{[1
]}

Irwin, Sean ^{[1
]}

Subramanian, Vanitha ^{[1
]}

Joshi, Jaya Julie ^{[1
]}

Wang, Chris K. ^{[2
,3
]}

Rimkunas, Victoria ^{[1
]}

Tortora, Davide ^{[2
,3
]}

Yang, Hua ^{[4
]}

Kumar, Namita ^{[4
]}

Kuznetsov, Galina ^{[4
]}

Matijevic, Mark ^{[4
]}

Chow, Jesse ^{[4
]}

Kumar, Pavan ^{[1
]}

Zou, Jian ^{[1
]}

Feala, Jacob ^{[1
]}

Corson, Laura ^{[1
]}

Henry, Ryan ^{[1
]}

Selvaraj, Anand ^{[1
]}

Davis, Allison ^{[1
]}

Bloudoff, Kristjan ^{[1
]}

Douglas, James ^{[5
]}

Kiss, Bernhard ^{[6
]}

Roberts, Morgan ^{[2
,3
]}

Fazli, Ladan ^{[2
,3
]}

Black, Peter C. ^{[2
,3
]}

Fekkes, Peter ^{[1
]}

Smith, Peter G. ^{[1
]}

Warmuth, Markus ^{[1
]}

Yu, Lihua ^{[1
]}

Hao, Ming-Hong ^{[1
]}

Larsen, Nicholas ^{[1
]}

Daugaard, Mads ^{[2
,3
]}

Zhu, Ping ^{[1
]}

机构：

[1] H3 Biomed Inc, 300 Technol Sq, Cambridge, MA 02139 USA

[2] Univ British Columbia, Dept Urol Sci, Vancouver, BC V5Z 1M9, Canada

[3] Vancouver Prostate Ctr, Vancouver, BC V6H 3Z6, Canada

[4] Eisai Inc, 4 Corp Dr, Andover, MA 01810 USA

[5] Univ Hosp Southampton, Dept Urol, Southampton SO16 6YD, Hants, England

[6] Univ Bern, Dept Urol, CH-3010 Bern, Switzerland

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

ACTIVATED RECEPTOR-GAMMA; IMMUNE CHECKPOINT BLOCKADE; TUMOR MICROENVIRONMENT; MOLECULAR-MECHANISMS; UROTHELIAL CANCER; PD-1; BLOCKADE; EXPRESSION; MUTATIONS; HETERODIMERIZATION; INFLAMMATION;

D O I：

10.1038/s41467-017-00147-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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

引用

页数：14

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