TY - JOUR
T1 - Transient ablation of regulatory T cells improves antitumor immunity in colitis-associated colon cancer
AU - Pastille, Eva
AU - Bardini, Katrin
AU - Fleissner, Diana
AU - Adamczyk, Alexandra
AU - Frede, Annika
AU - Wadwa, Munisch
AU - Von Smolinski, Dorthe
AU - Kasper, Stefan
AU - Sparwasser, Tim
AU - Gruber, Achim D.
AU - Schuler, Martin
AU - Sakaguchi, Shimon
AU - Roers, Axel
AU - Müller, Werner
AU - Hansen, Wiebke
AU - Buer, Jan
AU - Westendorf, Astrid M.
PY - 2014/8/15
Y1 - 2014/8/15
N2 - Regulatory T cells (Treg) are supportive to cancer development in most tissues, but their role in colitis-associated colon cancer (CAC) remains unclear. In this study, we investigated the role of CD4+Foxp3 + Treg in a mouse model of CAC and in patients with colon cancer. These Treg were increased strongly in number in a mouse model of CAC and in the peripheral blood of patients with colon cancer, exhibiting an activated phenotype as defined by elevated expression of GARP, CD103, CTLA-4, and IL10, along with an increased suppressive effect on the proliferation and Th1 cytokine expression of CD4+CD25- responder T cells ex vivo. Transient ablation of CD4+Foxp3+ Treg during tumor development in the CAC model suppressed tumor outgrowth and distribution, accompanied by an increased number of CD8+IFNγ/granzyme B-producing effector T cells. Conversely, inactivation of IL10 in Treg did not elevate the antitumor response but instead further boosted tumor development. Our results establish a tumor-promoting function for Treg during CAC formation, but they also suggest that a selective, transient ablation of Treg can evoke antitumor responses, with implications for immunotherapeutic interventions in patients with CAC. ©2014 AACR.
AB - Regulatory T cells (Treg) are supportive to cancer development in most tissues, but their role in colitis-associated colon cancer (CAC) remains unclear. In this study, we investigated the role of CD4+Foxp3 + Treg in a mouse model of CAC and in patients with colon cancer. These Treg were increased strongly in number in a mouse model of CAC and in the peripheral blood of patients with colon cancer, exhibiting an activated phenotype as defined by elevated expression of GARP, CD103, CTLA-4, and IL10, along with an increased suppressive effect on the proliferation and Th1 cytokine expression of CD4+CD25- responder T cells ex vivo. Transient ablation of CD4+Foxp3+ Treg during tumor development in the CAC model suppressed tumor outgrowth and distribution, accompanied by an increased number of CD8+IFNγ/granzyme B-producing effector T cells. Conversely, inactivation of IL10 in Treg did not elevate the antitumor response but instead further boosted tumor development. Our results establish a tumor-promoting function for Treg during CAC formation, but they also suggest that a selective, transient ablation of Treg can evoke antitumor responses, with implications for immunotherapeutic interventions in patients with CAC. ©2014 AACR.
U2 - 10.1158/0008-5472.CAN-13-3065
DO - 10.1158/0008-5472.CAN-13-3065
M3 - Article
C2 - 24906621
SN - 1538-7445
VL - 74
SP - 4258
EP - 4269
JO - Cancer Research
JF - Cancer Research
IS - 16
ER -
