RORγt-Expressing Tregs Drive the Growth of Colitis-Associated Colorectal Cancer by Controlling IL6 in Dendritic Cells

Autor: Rita Carsetti, Giovanni Monteleone, Claudia Mescoli, Massimo Fantini, Angelamaria Rizzo, Massimo Rugge, Angela Ortenzi, Carmine Stolfi, Eleonora Franzè, Ezio Giorda, Alfredo Colantoni, Martina Di Giovangiulio, Hans-Joerg Fehling
Rok vydání: 2018
Předmět:
Male
0301 basic medicine
Cancer Research
medicine.medical_treatment
Immunology
Population
Azoxymethane
chemical and pharmacologic phenomena
Inflammation
Biology
T-Lymphocytes
Regulatory
Proinflammatory cytokine
Settore MED/12
03 medical and health sciences
Lymphocytes
Tumor-Infiltrating
0302 clinical medicine
RAR-related orphan receptor gamma
Conditional gene knockout
medicine
Animals
Humans
Gene silencing
CTLA-4 Antigen
Gene Silencing
RNA
Small Interfering
education
Mice
Knockout
education.field_of_study
Interleukin-6
Settore BIO/12
Dextran Sulfate
Forkhead Box Protein O3
FOXP3
hemic and immune systems
Dendritic Cells
Nuclear Receptor Subfamily 1
Group F
Member 3
Colitis
Mice
Inbred C57BL
030104 developmental biology
Cytokine
030220 oncology & carcinogenesis
Cancer research
medicine.symptom
Colorectal Neoplasms
Zdroj: Cancer Immunology Research. 6:1082-1092
ISSN: 2326-6074
2326-6066
DOI: 10.1158/2326-6066.cir-17-0698
Popis: 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.
Databáze: OpenAIRE
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