Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer.

Nichole R. Blatner*, Mary F. Mulcahy, Kristen L. Dennis, Denise Scholtens, David J. Bentrem, Joseph D. Phillips, Soo Ham, Barry P. Sandall, Mohammad W. Khan, David M. Mahvi, Amy L. Halverson, Steven J. Stryker, Anne Marie Boller, Ashima Singal, Rebekka K. Sneed, Bara Sarraj, Mohammed Javeed Ansari, Martin Oft, Yoichiro Iwakura, Liang Zhou & 4 others Andreas Bonertz, Philipp Beckhove, Fotini Gounari, Khashayarsha Khazaie

*Corresponding author for this work

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

The role of regulatory T cells (T(regs)) in human colon cancer (CC) remains controversial: high densities of tumor-infiltrating T(regs) can correlate with better or worse clinical outcomes depending on the study. In mouse models of cancer, T(regs) have been reported to suppress inflammation and protect the host, suppress T cells and protect the tumor, or even have direct cancer-promoting attributes. These different effects may result from the presence of different T(reg) subsets. We report the preferential expansion of a T(reg) subset in human CC with potent T cell-suppressive, but compromised anti-inflammatory, properties; these cells are distinguished from T(regs) present in healthy donors by their coexpression of Foxp3 and RORγt. T(regs) with similar attributes were found to be expanded in mouse models of hereditary polyposis. Indeed, ablation of the RORγt gene in Foxp3(+) cells in polyp-prone mice stabilized T(reg) anti-inflammatory functions, suppressed inflammation, improved polyp-specific immune surveillance, and severely attenuated polyposis. Ablation of interleukin-6 (IL-6), IL-23, IL-17, or tumor necrosis factor-α in polyp-prone mice reduced polyp number but not to the same extent as loss of RORγt. Surprisingly, loss of IL-17A had a dual effect: IL-17A-deficient mice had fewer polyps but continued to have RORγt(+) T(regs) and developed invasive cancer. Thus, we conclude that RORγt has a central role in determining the balance between protective and pathogenic T(regs) in CC and that T(reg) subtype regulates inflammation, potency of immune surveillance, and severity of disease outcome.

Original languageEnglish (US)
JournalScience translational medicine
Volume4
Issue number164
StatePublished - Jan 1 2012

Fingerprint

T-Lymphocyte Subsets
Regulatory T-Lymphocytes
Polyps
Colonic Neoplasms
Interleukin-17
Neoplasms
Inflammation
Anti-Inflammatory Agents
Interleukin-23
T-Lymphocytes
Interleukin-6
Tumor Necrosis Factor-alpha
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Blatner, Nichole R. ; Mulcahy, Mary F. ; Dennis, Kristen L. ; Scholtens, Denise ; Bentrem, David J. ; Phillips, Joseph D. ; Ham, Soo ; Sandall, Barry P. ; Khan, Mohammad W. ; Mahvi, David M. ; Halverson, Amy L. ; Stryker, Steven J. ; Boller, Anne Marie ; Singal, Ashima ; Sneed, Rebekka K. ; Sarraj, Bara ; Ansari, Mohammed Javeed ; Oft, Martin ; Iwakura, Yoichiro ; Zhou, Liang ; Bonertz, Andreas ; Beckhove, Philipp ; Gounari, Fotini ; Khazaie, Khashayarsha. / Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer. In: Science translational medicine. 2012 ; Vol. 4, No. 164.
@article{2a859094d18a4b3bbcbf06fcf3a0e33b,
title = "Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer.",
abstract = "The role of regulatory T cells (T(regs)) in human colon cancer (CC) remains controversial: high densities of tumor-infiltrating T(regs) can correlate with better or worse clinical outcomes depending on the study. In mouse models of cancer, T(regs) have been reported to suppress inflammation and protect the host, suppress T cells and protect the tumor, or even have direct cancer-promoting attributes. These different effects may result from the presence of different T(reg) subsets. We report the preferential expansion of a T(reg) subset in human CC with potent T cell-suppressive, but compromised anti-inflammatory, properties; these cells are distinguished from T(regs) present in healthy donors by their coexpression of Foxp3 and RORγt. T(regs) with similar attributes were found to be expanded in mouse models of hereditary polyposis. Indeed, ablation of the RORγt gene in Foxp3(+) cells in polyp-prone mice stabilized T(reg) anti-inflammatory functions, suppressed inflammation, improved polyp-specific immune surveillance, and severely attenuated polyposis. Ablation of interleukin-6 (IL-6), IL-23, IL-17, or tumor necrosis factor-α in polyp-prone mice reduced polyp number but not to the same extent as loss of RORγt. Surprisingly, loss of IL-17A had a dual effect: IL-17A-deficient mice had fewer polyps but continued to have RORγt(+) T(regs) and developed invasive cancer. Thus, we conclude that RORγt has a central role in determining the balance between protective and pathogenic T(regs) in CC and that T(reg) subtype regulates inflammation, potency of immune surveillance, and severity of disease outcome.",
author = "Blatner, {Nichole R.} and Mulcahy, {Mary F.} and Dennis, {Kristen L.} and Denise Scholtens and Bentrem, {David J.} and Phillips, {Joseph D.} and Soo Ham and Sandall, {Barry P.} and Khan, {Mohammad W.} and Mahvi, {David M.} and Halverson, {Amy L.} and Stryker, {Steven J.} and Boller, {Anne Marie} and Ashima Singal and Sneed, {Rebekka K.} and Bara Sarraj and Ansari, {Mohammed Javeed} and Martin Oft and Yoichiro Iwakura and Liang Zhou and Andreas Bonertz and Philipp Beckhove and Fotini Gounari and Khashayarsha Khazaie",
year = "2012",
month = "1",
day = "1",
language = "English (US)",
volume = "4",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "164",

}

Blatner, NR, Mulcahy, MF, Dennis, KL, Scholtens, D, Bentrem, DJ, Phillips, JD, Ham, S, Sandall, BP, Khan, MW, Mahvi, DM, Halverson, AL, Stryker, SJ, Boller, AM, Singal, A, Sneed, RK, Sarraj, B, Ansari, MJ, Oft, M, Iwakura, Y, Zhou, L, Bonertz, A, Beckhove, P, Gounari, F & Khazaie, K 2012, 'Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer.', Science translational medicine, vol. 4, no. 164.

Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer. / Blatner, Nichole R.; Mulcahy, Mary F.; Dennis, Kristen L.; Scholtens, Denise; Bentrem, David J.; Phillips, Joseph D.; Ham, Soo; Sandall, Barry P.; Khan, Mohammad W.; Mahvi, David M.; Halverson, Amy L.; Stryker, Steven J.; Boller, Anne Marie; Singal, Ashima; Sneed, Rebekka K.; Sarraj, Bara; Ansari, Mohammed Javeed; Oft, Martin; Iwakura, Yoichiro; Zhou, Liang; Bonertz, Andreas; Beckhove, Philipp; Gounari, Fotini; Khazaie, Khashayarsha.

In: Science translational medicine, Vol. 4, No. 164, 01.01.2012.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer.

AU - Blatner, Nichole R.

AU - Mulcahy, Mary F.

AU - Dennis, Kristen L.

AU - Scholtens, Denise

AU - Bentrem, David J.

AU - Phillips, Joseph D.

AU - Ham, Soo

AU - Sandall, Barry P.

AU - Khan, Mohammad W.

AU - Mahvi, David M.

AU - Halverson, Amy L.

AU - Stryker, Steven J.

AU - Boller, Anne Marie

AU - Singal, Ashima

AU - Sneed, Rebekka K.

AU - Sarraj, Bara

AU - Ansari, Mohammed Javeed

AU - Oft, Martin

AU - Iwakura, Yoichiro

AU - Zhou, Liang

AU - Bonertz, Andreas

AU - Beckhove, Philipp

AU - Gounari, Fotini

AU - Khazaie, Khashayarsha

PY - 2012/1/1

Y1 - 2012/1/1

N2 - The role of regulatory T cells (T(regs)) in human colon cancer (CC) remains controversial: high densities of tumor-infiltrating T(regs) can correlate with better or worse clinical outcomes depending on the study. In mouse models of cancer, T(regs) have been reported to suppress inflammation and protect the host, suppress T cells and protect the tumor, or even have direct cancer-promoting attributes. These different effects may result from the presence of different T(reg) subsets. We report the preferential expansion of a T(reg) subset in human CC with potent T cell-suppressive, but compromised anti-inflammatory, properties; these cells are distinguished from T(regs) present in healthy donors by their coexpression of Foxp3 and RORγt. T(regs) with similar attributes were found to be expanded in mouse models of hereditary polyposis. Indeed, ablation of the RORγt gene in Foxp3(+) cells in polyp-prone mice stabilized T(reg) anti-inflammatory functions, suppressed inflammation, improved polyp-specific immune surveillance, and severely attenuated polyposis. Ablation of interleukin-6 (IL-6), IL-23, IL-17, or tumor necrosis factor-α in polyp-prone mice reduced polyp number but not to the same extent as loss of RORγt. Surprisingly, loss of IL-17A had a dual effect: IL-17A-deficient mice had fewer polyps but continued to have RORγt(+) T(regs) and developed invasive cancer. Thus, we conclude that RORγt has a central role in determining the balance between protective and pathogenic T(regs) in CC and that T(reg) subtype regulates inflammation, potency of immune surveillance, and severity of disease outcome.

AB - The role of regulatory T cells (T(regs)) in human colon cancer (CC) remains controversial: high densities of tumor-infiltrating T(regs) can correlate with better or worse clinical outcomes depending on the study. In mouse models of cancer, T(regs) have been reported to suppress inflammation and protect the host, suppress T cells and protect the tumor, or even have direct cancer-promoting attributes. These different effects may result from the presence of different T(reg) subsets. We report the preferential expansion of a T(reg) subset in human CC with potent T cell-suppressive, but compromised anti-inflammatory, properties; these cells are distinguished from T(regs) present in healthy donors by their coexpression of Foxp3 and RORγt. T(regs) with similar attributes were found to be expanded in mouse models of hereditary polyposis. Indeed, ablation of the RORγt gene in Foxp3(+) cells in polyp-prone mice stabilized T(reg) anti-inflammatory functions, suppressed inflammation, improved polyp-specific immune surveillance, and severely attenuated polyposis. Ablation of interleukin-6 (IL-6), IL-23, IL-17, or tumor necrosis factor-α in polyp-prone mice reduced polyp number but not to the same extent as loss of RORγt. Surprisingly, loss of IL-17A had a dual effect: IL-17A-deficient mice had fewer polyps but continued to have RORγt(+) T(regs) and developed invasive cancer. Thus, we conclude that RORγt has a central role in determining the balance between protective and pathogenic T(regs) in CC and that T(reg) subtype regulates inflammation, potency of immune surveillance, and severity of disease outcome.

UR - http://www.scopus.com/inward/record.url?scp=84879401216&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879401216&partnerID=8YFLogxK

M3 - Article

VL - 4

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 164

ER -