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

Ziming Wang, Ethan G. Aguilar, Jesus I. Luna, Cordelia Dunai, Lam T. Khuat, Catherine T. Le, Annie Mirsoian, Christine M. Minnar, Kevin M. Stoffel, Ian R. Sturgill, Steven K. Grossenbacher, Sita S. Withers, Robert B Rebhun, Dennis Hartigan-O'Connor, Gema Méndez-Lagares, Alice F Tarantal, Roslyn Rivkah Isseroff, Thomas S. Griffith, Kurt A. Schalper, Alexander MerleevAsim Saha, Emanual Michael Maverakis, Karen Kelly, Raid Aljumaily, Sami Ibrahimi, Sarbajit Mukherjee, Michael Machiorlatti, Sara K. Vesely, Dan L. Longo, Bruce R. Blazar, Robert J Canter, William J Murphy, Arta M Monjazeb

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalNature Medicine
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

T-cells
Tumors
Obesity
T-Lymphocytes
Neoplasms
Immunotherapy
Bearings (structural)
Oncology
Tumor Biomarkers
Leptin
Aging of materials
Pandemics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. / Wang, Ziming; Aguilar, Ethan G.; Luna, Jesus I.; Dunai, Cordelia; Khuat, Lam T.; Le, Catherine T.; Mirsoian, Annie; Minnar, Christine M.; Stoffel, Kevin M.; Sturgill, Ian R.; Grossenbacher, Steven K.; Withers, Sita S.; Rebhun, Robert B; Hartigan-O'Connor, Dennis; Méndez-Lagares, Gema; Tarantal, Alice F; Isseroff, Roslyn Rivkah; Griffith, Thomas S.; Schalper, Kurt A.; Merleev, Alexander; Saha, Asim; Maverakis, Emanual Michael; Kelly, Karen; Aljumaily, Raid; Ibrahimi, Sami; Mukherjee, Sarbajit; Machiorlatti, Michael; Vesely, Sara K.; Longo, Dan L.; Blazar, Bruce R.; Canter, Robert J; Murphy, William J; Monjazeb, Arta M.

In: Nature Medicine, 01.01.2018.

Research output: Contribution to journalArticle

Wang, Z, Aguilar, EG, Luna, JI, Dunai, C, Khuat, LT, Le, CT, Mirsoian, A, Minnar, CM, Stoffel, KM, Sturgill, IR, Grossenbacher, SK, Withers, SS, Rebhun, RB, Hartigan-O'Connor, D, Méndez-Lagares, G, Tarantal, AF, Isseroff, RR, Griffith, TS, Schalper, KA, Merleev, A, Saha, A, Maverakis, EM, Kelly, K, Aljumaily, R, Ibrahimi, S, Mukherjee, S, Machiorlatti, M, Vesely, SK, Longo, DL, Blazar, BR, Canter, RJ, Murphy, WJ & Monjazeb, AM 2018, 'Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade', Nature Medicine. https://doi.org/10.1038/s41591-018-0221-5
Wang, Ziming ; Aguilar, Ethan G. ; Luna, Jesus I. ; Dunai, Cordelia ; Khuat, Lam T. ; Le, Catherine T. ; Mirsoian, Annie ; Minnar, Christine M. ; Stoffel, Kevin M. ; Sturgill, Ian R. ; Grossenbacher, Steven K. ; Withers, Sita S. ; Rebhun, Robert B ; Hartigan-O'Connor, Dennis ; Méndez-Lagares, Gema ; Tarantal, Alice F ; Isseroff, Roslyn Rivkah ; Griffith, Thomas S. ; Schalper, Kurt A. ; Merleev, Alexander ; Saha, Asim ; Maverakis, Emanual Michael ; Kelly, Karen ; Aljumaily, Raid ; Ibrahimi, Sami ; Mukherjee, Sarbajit ; Machiorlatti, Michael ; Vesely, Sara K. ; Longo, Dan L. ; Blazar, Bruce R. ; Canter, Robert J ; Murphy, William J ; Monjazeb, Arta M. / Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. In: Nature Medicine. 2018.
@article{a19ed32f288b4f86b4ba078354404f5b,
title = "Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade",
abstract = "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.",
author = "Ziming Wang and Aguilar, {Ethan G.} and Luna, {Jesus I.} and Cordelia Dunai and Khuat, {Lam T.} and Le, {Catherine T.} and Annie Mirsoian and Minnar, {Christine M.} and Stoffel, {Kevin M.} and Sturgill, {Ian R.} and Grossenbacher, {Steven K.} and Withers, {Sita S.} and Rebhun, {Robert B} and Dennis Hartigan-O'Connor and Gema M{\'e}ndez-Lagares and Tarantal, {Alice F} and Isseroff, {Roslyn Rivkah} and Griffith, {Thomas S.} and Schalper, {Kurt A.} and Alexander Merleev and Asim Saha and Maverakis, {Emanual Michael} and Karen Kelly and Raid Aljumaily and Sami Ibrahimi and Sarbajit Mukherjee and Michael Machiorlatti and Vesely, {Sara K.} and Longo, {Dan L.} and Blazar, {Bruce R.} and Canter, {Robert J} and Murphy, {William J} and Monjazeb, {Arta M}",
year = "2018",
month = "1",
day = "1",
doi = "10.1038/s41591-018-0221-5",
language = "English (US)",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade

AU - Wang, Ziming

AU - Aguilar, Ethan G.

AU - Luna, Jesus I.

AU - Dunai, Cordelia

AU - Khuat, Lam T.

AU - Le, Catherine T.

AU - Mirsoian, Annie

AU - Minnar, Christine M.

AU - Stoffel, Kevin M.

AU - Sturgill, Ian R.

AU - Grossenbacher, Steven K.

AU - Withers, Sita S.

AU - Rebhun, Robert B

AU - Hartigan-O'Connor, Dennis

AU - Méndez-Lagares, Gema

AU - Tarantal, Alice F

AU - Isseroff, Roslyn Rivkah

AU - Griffith, Thomas S.

AU - Schalper, Kurt A.

AU - Merleev, Alexander

AU - Saha, Asim

AU - Maverakis, Emanual Michael

AU - Kelly, Karen

AU - Aljumaily, Raid

AU - Ibrahimi, Sami

AU - Mukherjee, Sarbajit

AU - Machiorlatti, Michael

AU - Vesely, Sara K.

AU - Longo, Dan L.

AU - Blazar, Bruce R.

AU - Canter, Robert J

AU - Murphy, William J

AU - Monjazeb, Arta M

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85056466975&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056466975&partnerID=8YFLogxK

U2 - 10.1038/s41591-018-0221-5

DO - 10.1038/s41591-018-0221-5

M3 - Article

C2 - 30420753

AN - SCOPUS:85056466975

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

ER -