Interleukin 12 stimulates IFN-γ-mediated inhibition of tumor-induced regulatory T-cell proliferation and enhances tumor clearance

Xuefang Cao, Karen Leonard, Lynne I. Collins, Sheng F. Cai, Joshua C. Mayer, Jacqueline E. Payton, Michael J. Walter, David Piwnica-Worms, Robert D. Schreiber, Timothy J. Ley

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

To define the factors that modulate regulatory T (Treg) cells in the tumor setting, we cocultured various tumor cells with either purified Treg cells, or with unfractionated splenocytes. We found that Treg expansion occurred only with unfractionated splenocytes, suggesting that accessory cells and/or factors produced by them play an essential role in tumorinduced Treg expansion. We performed gene expression profiling on tumor-associated Treg cells to identify candidate signaling molecules and studied their effects on tumorinduced Treg expansion. We inadvertently discovered that interleukin (IL)-12 treatment blocked Treg expansion in an IL-12 receptor-dependent fashion. Additional studies showed that IL-12 acts by stimulating IFN- γ mediated inhibition of Treg cell proliferation, which may partially account for the antitumor effects of IL-12. Furthermore, IL-12 treatment was found to decrease IL-2 production, which may lead to IFN-γ-independent inhibition of Treg cells, as IL-2 is required for their survival and expansion. Mechanistic studies revealed that IFN- γ signaling directly causes cell cycle arrest in Treg cells. This study shows that an IL-12-IFN-γ axis can suppress tumor-induced Treg proliferation. This mechanism may counteract the ability of Treg cells to promote tumor growth in vivo.

Original languageEnglish
Pages (from-to)8700-8709
Number of pages10
JournalCancer research
Volume69
Issue number22
DOIs
StatePublished - Nov 15 2009

Fingerprint Dive into the research topics of 'Interleukin 12 stimulates IFN-γ-mediated inhibition of tumor-induced regulatory T-cell proliferation and enhances tumor clearance'. Together they form a unique fingerprint.

Cite this