title: Normalizing Microbiota-Induced Retinoic Acid Deficiency Stimulates Protective CD8(+) T Cell-Mediated Immunity in Colorectal Cancer.
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(+) 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.
authors: Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA. Electronic address: nupur26@stanford.edu.
authors: Nupur
authors: N
authors: Bhattacharya
authors: Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA.
authors: Robert
authors: R
authors: Yuan
authors: 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.
authors: Tyler R
authors: TR
authors: Prestwood
authors: Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA.
authors: Hweixian Leong
authors: HL
authors: Penny
authors: Department of Pathology, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors: Michael A
authors: MA
authors: DiMaio
authors: Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA.
authors: Nathan E
authors: NE
authors: Reticker-Flynn
authors: Graduate Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors: Charles R
authors: CR
authors: Krois
authors: Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA.
authors: Justin A
authors: JA
authors: Kenkel
authors: Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA.
authors: Tho D
authors: TD
authors: Pham
authors: Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA.
authors: Yaron
authors: Y
authors: Carmi
authors: Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA.
authors: Lorna
authors: L
authors: Tolentino
authors: Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA.
authors: Okmi
authors: O
authors: Choi
authors: Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA.
authors: Reyna
authors: R
authors: Hulett
authors: Graduate Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors: Jinshan
authors: J
authors: Wang
authors: Department of Pathology, University Health Network, and Departments of Laboratory Medicine and Pathobiology, and Immunology, University of Toronto, Toronto, ON M5G 2N2, Canada.
authors: Daniel A
authors: DA
authors: Winer
authors: Graduate Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors: Joseph L
authors: JL
authors: Napoli
authors: Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA. Electronic address: edgareng@stanford.edu.
authors: Edgar G
authors: EG
authors: Engleman
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D063646:Carcinogenesis / Q000276:immunology; D003106:Colon / Q000276:immunology / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota / Q000276:immunology*; D000072516:Retinoic Acid 4-Hydroxylase / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014212:Tretinoin / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D014212:Tretinoin; D000072516:Retinoic Acid 4-Hydroxylase