TY - JOUR
T1 - Interleukin 12 stimulates IFN-γ-mediated inhibition of tumor-induced regulatory T-cell proliferation and enhances tumor clearance
AU - Cao, Xuefang
AU - Leonard, Karen
AU - Collins, Lynne I.
AU - Cai, Sheng F.
AU - Mayer, Joshua C.
AU - Payton, Jacqueline E.
AU - Walter, Michael J.
AU - Piwnica-Worms, David
AU - Schreiber, Robert D.
AU - Ley, Timothy J.
PY - 2009/11/15
Y1 - 2009/11/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=72249083705&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-09-1145
DO - 10.1158/0008-5472.CAN-09-1145
M3 - Article
C2 - 19843867
AN - SCOPUS:72249083705
SN - 0008-5472
VL - 69
SP - 8700
EP - 8709
JO - Cancer research
JF - Cancer research
IS - 22
ER -