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Normalizing Microbiota-Induced Retinoic Acid Deficiency Stimulates Protective CD8 + T Cell-Mediated Immunity in Colorectal Cancer
- Source :
- Immunity, vol 45, iss 3
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
Abstract
- Although all-trans-retinoic acid (atRA) is a key regulator of intestinal immunity, its role in colorectal cancer (CRC) is unknown. We found that mice with colitis-associated CRC had a marked deficiency in colonic atRA due to alterations in atRA metabolism mediated by microbiota-induced intestinal inflammation. Human ulcerative colitis (UC), UC-associated CRC, and sporadic CRC specimens have similar alterations in atRA metabolic enzymes, consistent with reduced colonic atRA. Inhibition of atRA signaling promoted tumorigenesis, whereas atRA supplementation reduced tumor burden. The benefit of atRA treatment was mediated by cytotoxic CD8(+) Tcells, which were activated due to MHCI upregulation on tumor cells. Consistent with these findings, increased colonic expression of the atRA-catabolizing enzyme, CYP26A1, correlated with reduced frequencies of tumoral cytotoxic CD8(+) Tcells and with worse disease prognosis in human CRC. These results reveal a mechanism by which microbiota drive colon carcinogenesis and highlight atRA metabolism as a therapeutic target for CRC.
- Subjects :
- 0301 basic medicine
Carcinogenesis
Colorectal cancer
Retinoic acid
CD8-Positive T-Lymphocytes
Inbred C57BL
medicine.disease_cause
Mice
chemistry.chemical_compound
0302 clinical medicine
2.1 Biological and endogenous factors
Immunology and Allergy
Cytotoxic T cell
Aetiology
Cancer
Microbiota
Retinoic Acid 4-Hydroxylase
Up-Regulation
Colo-Rectal Cancer
Infectious Diseases
030220 oncology & carcinogenesis
Female
Colorectal Neoplasms
Signal Transduction
Colon
Immunology
Tretinoin
Biology
Autoimmune Disease
Article
03 medical and health sciences
CYP26A1
Downregulation and upregulation
Immunity
medicine
Animals
Humans
neoplasms
Nutrition
Prevention
organic chemicals
Inflammatory Bowel Disease
medicine.disease
digestive system diseases
biological factors
Mice, Inbred C57BL
030104 developmental biology
chemistry
Cancer research
Digestive Diseases
CD8
Subjects
Details
- ISSN :
- 10747613
- Volume :
- 45
- Database :
- OpenAIRE
- Journal :
- Immunity
- Accession number :
- edsair.doi.dedup.....bf46f3e18054d114728fb477a93d579e