Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade

被引：593

作者：

Wang, Ziming ^{[1
]}

Aguilar, Ethan G. ^{[1
]}

Luna, Jesus I. ^{[1
]}

Dunai, Cordelia ^{[1
]}

Khuat, Lam T. ^{[1
]}

Le, Catherine T. ^{[1
]}

Mirsoian, Annie ^{[1
]}

Minnar, Christine M. ^{[1
]}

Stoffel, Kevin M. ^{[1
]}

Sturgill, Ian R. ^{[1
]}

Grossenbacher, Steven K. ^{[1
]}

Withers, Sita S. ^{[2
]}

Rebhun, Robert B. ^{[2
]}

Hartigan-O'Connor, Dennis J. ^{[3
,4
,5
]}

Mendez-Lagares, Gema ^{[4
,5
]}

Tarantal, Alice F. ^{[5
,6
,7
]}

Isseroff, R. Rivkah ^{[1
,8
]}

Griffith, Thomas S. ^{[9
,10
]}

Schalper, Kurt A. ^{[11
,12
]}

Merleev, Alexander ^{[1
,13
]}

Saha, Asim ^{[14
,15
]}

Maverakis, Emanual ^{[1
,13
]}

Kelly, Karen ^{[16
]}

Aljumaily, Raid ^{[17
]}

Ibrahimi, Sami ^{[17
]}

Mukherjee, Sarbajit ^{[17
]}

Machiorlatti, Michael ^{[18
]}

Vesely, Sara K. ^{[18
]}

Longo, Dan L. ^{[19
]}

Blazar, Bruce R. ^{[14
,20
]}

Canter, Robert J. ^{[21
]}

Murphy, William J. ^{[1
,16
]}

Monjazeb, Arta M. ^{[22
]}

机构：

[1] Univ Calif Davis, Sch Med, Dept Dermatol, Sacramento, CA 95817 USA

[2] Univ Calif Davis, Sch Vet Med, Dept Surg & Radiol Sci, Davis, CA 95616 USA

[3] Univ Calif San Francisco, Div Expt Med, San Francisco, CA 94143 USA

[4] Univ Calif Davis, Dept Med Microbiol & Immunol, Davis, CA 95616 USA

[5] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA

[6] Univ Calif Davis, Sch Med, Dept Pediat, Davis, CA 95616 USA

[7] Univ Calif Davis, Dept Cell Biol & Human Anat, Davis, CA 95616 USA

[8] Sacramento VA Med Ctr, Dermatol Serv, Mather, CA USA

[9] Univ Minnesota, Dept Urol, Ctr Immunol, Masonic Canc Ctr,Microbiol,Immunol, Minneapolis, MN USA

[10] Univ Minnesota, Canc Biol Grad Program, Minneapolis, MN USA

[11] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA

[12] Yale Univ, Sch Med, Translat Immunooncol Lab, New Haven, CT 06510 USA

[13] Univ Calif Davis, Immune Monitoring Core, Comprehens Canc Ctr, Sacramento, CA 95817 USA

[14] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA

[15] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA

[16] Univ Calif Davis, Sch Med, Div Hematol & Oncol, Dept Internal Med, Sacramento, CA 95817 USA

[17] Univ Oklahoma, Hlth Sci Ctr, Dept Internal Med, Sect Hematol & Oncol, Oklahoma City, OK USA

[18] Univ Oklahoma, Hlth Sci Ctr, Dept Biostat & Epidemiol, Oklahoma City, OK USA

[19] NIA, Lab Genet & Genom, NIH, Baltimore, MD 21224 USA

[20] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA

[21] Univ Calif Davis, Sch Med, Dept Surg, Div Surg Oncol,Comprehens Canc Ctr, Sacramento, CA 95817 USA

[22] Univ Calif Davis, Comprehens Canc Ctr, Sch Med, Dept Radiat Oncol, Sacramento, CA 95817 USA

来源：

NATURE MEDICINE | 2019年 / 25卷 / 01期

关键词：

INHIBITORY RECEPTOR PD-1; BODY-MASS INDEX; LEPTIN RESISTANCE; IMMUNE-RESPONSE; EXHAUSTION; STAT3; IMMUNOTHERAPY; PEMBROLIZUMAB; INFLAMMATION; SENSITIVITY;

D O I：

10.1038/s41591-018-0221-5

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity.

引用

页码：141 / +

页数：13

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