Normalizing Microbiota-Induced Retinoic Acid Deficiency Stimulates Protective CD8(+) T Cell-Mediated Immunity in Colorectal Cancer.

Autor:	Bhattacharya N; Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA. Electronic address: nupur26@stanford.edu., Yuan R; Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA., Prestwood TR; Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA., Penny HL; Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA., DiMaio MA; Department of Pathology, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA., Reticker-Flynn NE; Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA., Krois CR; Graduate Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA., Kenkel JA; Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA., Pham TD; Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA., Carmi Y; Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA., Tolentino L; Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA., Choi O; Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA., Hulett R; Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA., Wang J; Graduate Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA., Winer DA; Department of Pathology, University Health Network, and Departments of Laboratory Medicine and Pathobiology, and Immunology, University of Toronto, Toronto, ON M5G 2N2, Canada., Napoli JL; Graduate Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA., Engleman EG; Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA. Electronic address: edgareng@stanford.edu.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2016 Sep 20; Vol. 45 (3), pp. 641-655. Date of Electronic Publication: 2016 Aug 30.
DOI:	10.1016/j.immuni.2016.08.008
Abstrakt:	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(+) T cells, 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(+) T cells 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. (Copyright © 2016 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu