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 ZhouAndreas Bonertz, Philipp Beckhove, Fotini Gounari, Khashayarsha Khazaie

*Corresponding author for this work

Research output: Contribution to journalArticle

116 Scopus citations

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 - Dec 12 2012

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer.'. Together they form a unique fingerprint.

  • Cite this

    Blatner, N. R., Mulcahy, M. F., Dennis, K. L., Scholtens, D., Bentrem, D. J., Phillips, J. D., Ham, S., Sandall, B. P., Khan, M. W., Mahvi, D. M., Halverson, A. L., Stryker, S. J., Boller, A. M., Singal, A., Sneed, R. K., Sarraj, B., Ansari, M. J., Oft, M., Iwakura, Y., ... Khazaie, K. (2012). Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer. Science translational medicine, 4(164).