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

Research output: Contribution to journal › Journal article › Research › peer-review

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Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer. / Korpal, Manav; Puyang, Xiaoling; Wu, Zhenhua Jeremy; Seiler, Roland; Furman, Craig; Oo, Htoo Zarni; Seiler, Michael; Irwin, Sean; Subramanian, Vanitha; Joshi, Jaya Julie; Wang, Chris Kedong; Rimkunas, Victoria; Tortora, Davide; Yang, Hua; Kumar, Namita; Kuznetsov, Galina; Matijevic, Mark; Chow, Jess; Kumar, Pavan; Zou, Jian; Feala, Jacob; Corson, Laura; Henry, Ryan; Selvaraj, Anand; Davis, Allison; Bloudoff, Kristjan; Douglas, James; Kiss, Bernhard; Roberts, Morgan E.; Fazli, Ladan; Black, Peter C; Fekkes, Peter; Smith, Peter G; Warmuth, Markus; Yu, Linhua; Hao, Ming-Hong; Larsen, Nicholas; Daugaard, Mads; Zhu, Ping.

In: Nature Communications, Vol. 8, 103, 2017.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Korpal, M, Puyang, X, Wu, ZJ, Seiler, R, Furman, C, Oo, HZ, Seiler, M, Irwin, S, Subramanian, V, Joshi, JJ, Wang, CK, Rimkunas, V, Tortora, D, Yang, H, Kumar, N, Kuznetsov, G, Matijevic, M, Chow, J, Kumar, P, Zou, J, Feala, J, Corson, L, Henry, R, Selvaraj, A, Davis, A, Bloudoff, K, Douglas, J, Kiss, B, Roberts, ME, Fazli, L, Black, PC, Fekkes, P, Smith, PG, Warmuth, M, Yu, L, Hao, M-H, Larsen, N, Daugaard, M & Zhu, P 2017, 'Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer', Nature Communications, vol. 8, 103. https://doi.org/10.1038/s41467-017-00147-w

APA

Korpal, M., Puyang, X., Wu, Z. J., Seiler, R., Furman, C., Oo, H. Z., Seiler, M., Irwin, S., Subramanian, V., Joshi, J. J., Wang, C. K., Rimkunas, V., Tortora, D., Yang, H., Kumar, N., Kuznetsov, G., Matijevic, M., Chow, J., Kumar, P., ... Zhu, P. (2017). Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer. Nature Communications, 8, [103]. https://doi.org/10.1038/s41467-017-00147-w

Vancouver

Korpal M, Puyang X, Wu ZJ, Seiler R, Furman C, Oo HZ et al. Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer. Nature Communications. 2017;8. 103. https://doi.org/10.1038/s41467-017-00147-w

Author

Korpal, Manav ; Puyang, Xiaoling ; Wu, Zhenhua Jeremy ; Seiler, Roland ; Furman, Craig ; Oo, Htoo Zarni ; Seiler, Michael ; Irwin, Sean ; Subramanian, Vanitha ; Joshi, Jaya Julie ; Wang, Chris Kedong ; Rimkunas, Victoria ; Tortora, Davide ; Yang, Hua ; Kumar, Namita ; Kuznetsov, Galina ; Matijevic, Mark ; Chow, Jess ; Kumar, Pavan ; Zou, Jian ; Feala, Jacob ; Corson, Laura ; Henry, Ryan ; Selvaraj, Anand ; Davis, Allison ; Bloudoff, Kristjan ; Douglas, James ; Kiss, Bernhard ; Roberts, Morgan E. ; Fazli, Ladan ; Black, Peter C ; Fekkes, Peter ; Smith, Peter G ; Warmuth, Markus ; Yu, Linhua ; Hao, Ming-Hong ; Larsen, Nicholas ; Daugaard, Mads ; Zhu, Ping. / Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer. In: Nature Communications. 2017 ; Vol. 8.

Bibtex

@article{f6d050e1d94344b9a1337ea5a342287c,
title = "Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα 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 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.",
author = "Manav Korpal and Xiaoling Puyang and Wu, {Zhenhua Jeremy} and Roland Seiler and Craig Furman and Oo, {Htoo Zarni} and Michael Seiler and Sean Irwin and Vanitha Subramanian and Joshi, {Jaya Julie} and Wang, {Chris Kedong} and Victoria Rimkunas and Davide Tortora and Hua Yang and Namita Kumar and Galina Kuznetsov and Mark Matijevic and Jess Chow and Pavan Kumar and Jian Zou and Jacob Feala and Laura Corson and Ryan Henry and Anand Selvaraj and Allison Davis and Kristjan Bloudoff and James Douglas and Bernhard Kiss and Roberts, {Morgan E.} and Ladan Fazli and Black, {Peter C} and Peter Fekkes and Smith, {Peter G} and Markus Warmuth and Linhua Yu and Ming-Hong Hao and Nicholas Larsen and Mads Daugaard and Ping Zhu",
year = "2017",
doi = "10.1038/s41467-017-00147-w",
language = "English",
volume = "8",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer

AU - Korpal, Manav

AU - Puyang, Xiaoling

AU - Wu, Zhenhua Jeremy

AU - Seiler, Roland

AU - Furman, Craig

AU - Oo, Htoo Zarni

AU - Seiler, Michael

AU - Irwin, Sean

AU - Subramanian, Vanitha

AU - Joshi, Jaya Julie

AU - Wang, Chris Kedong

AU - Rimkunas, Victoria

AU - Tortora, Davide

AU - Yang, Hua

AU - Kumar, Namita

AU - Kuznetsov, Galina

AU - Matijevic, Mark

AU - Chow, Jess

AU - Kumar, Pavan

AU - Zou, Jian

AU - Feala, Jacob

AU - Corson, Laura

AU - Henry, Ryan

AU - Selvaraj, Anand

AU - Davis, Allison

AU - Bloudoff, Kristjan

AU - Douglas, James

AU - Kiss, Bernhard

AU - Roberts, Morgan E.

AU - Fazli, Ladan

AU - Black, Peter C

AU - Fekkes, Peter

AU - Smith, Peter G

AU - Warmuth, Markus

AU - Yu, Linhua

AU - Hao, Ming-Hong

AU - Larsen, Nicholas

AU - Daugaard, Mads

AU - Zhu, Ping

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-017-00147-w

DO - 10.1038/s41467-017-00147-w

M3 - Journal article

VL - 8

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 103

ER -

ID: 316427128