Abstract
Chronic inflammation drives colitis-associated colorectal cancer (CAC) in inflammatory bowel disease (IBD). FoxP3+ regulatory T cells (Treg) coexpressing the Th17-related transcription factor RORγt accumulate in the lamina propria of IBD patients, where they are thought to represent an intermediate stage of development toward a Th17 proinflammatory phenotype. However, the role of these cells in CAC is unknown. RORγt+FoxP3+ cells were investigated in human samples of CAC, and their phenotypic stability and function were investigated in an azoxymethane/dextran sulfate sodium model of CAC using Treg fate-mapping reporter and Treg-specific RORγt conditional knockout mice. Tumor development and the intratumoral inflammatory milieu were characterized in these mice. The functional role of CTLA-4 expressed by Tregs and FoxO3 in dendritic cells (DC) was studied in vitro and in vivo by siRNA-silencing experiments. RORγt expression identified a phenotypically stable population of tumor-infiltrating Tregs in humans and mice. Conditional RORγt knockout mice showed reduced tumor incidence, and dysplastic cells exhibited low Ki67 expression and STAT3 activation. Tumor-infiltrating DCs produced less IL6, a cytokine that triggers STAT3-dependent proliferative signals in neoplastic cells. RORγt-deficient Tregs isolated from tumors overexpressed CTLA-4 and induced DCs to have elevated expression of the transcription factor FoxO3, thus reducing IL6 expression. Finally, in vivo silencing of FoxO3 obtained by siRNA microinjection in the tumors of RORγt-deficient mice restored IL6 expression and tumor growth. These data demonstrate that RORγt expressed by tumor-infiltrating Tregs sustains tumor growth by leaving IL6 expression in DCs unchecked. Cancer Immunol Res; 6(9); 1082-92. ©2018 AACR.
Highlights
Inflammatory bowel disease (IBD) is associated with an increased risk to develop colorectal cancer, and chronic inflammation has been shown to be the major driver of carcinogenesis [1, 2]
Regulatory T cells (Treg), characterized by the expression of the transcription factor FoxP3, play a key role in the maintenance of intestinal immune system homeostasis, and loss of these cells results in an uncontrolled activation of the immune system involving different organs including the gut [3, 4]
To assess whether this subset of T cells accumulated in CAC, colonic sections of human ulcerative colitis containing dysplastic areas were stained for FoxP3 and RORgt
Summary
Inflammatory bowel disease (IBD) is associated with an increased risk to develop colorectal cancer, and chronic inflammation has been shown to be the major driver of carcinogenesis [1, 2]. The role of Tregs in colitis-associated colorectal cancer (CAC) remains unclear. Data from sporadic colorectal cancer indicate that the accumulation of Tregs in the dysplastic areas is associated with both positive [5,6,7] and negative prognoses [8]. Tregs have been reported as capable of protecting the host from cancer by reducing the inflammation mediated by T cells. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).
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