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      Normalizing microbiota-induced retinoic acid deficiency stimulates protective CD8 + T-cell-mediated immunity in colorectal cancer

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          Summary

          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, 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.

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          Author and article information

          Journal
          9432918
          8591
          Immunity
          Immunity
          Immunity
          1074-7613
          1097-4180
          22 November 2016
          30 August 2016
          20 September 2016
          20 September 2017
          : 45
          : 3
          : 641-655
          Affiliations
          [1 ]Department of Pathology, Stanford University School of Medicine (Blood Center), 3373 Hillview Avenue, Palo Alto, CA 94304, USA
          [2 ]Department of Pathology, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA
          [3 ]Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
          [4 ]Department of Pathology, University Health Network, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada
          Author notes
          Corresponding Authors: Edgar G. Engleman and Nupur Bhattacharya, Stanford Blood Center, 3373 Hillview Avenue, Palo Alto, CA 94304, edgareng@ 123456stanford.edu and nupur26@ 123456stanford.edu , Phone: 650-723-7960, Fax: 650-725-0592
          [5]

          Co-first authors

          Article
          PMC5132405 PMC5132405 5132405 nihpa810650
          10.1016/j.immuni.2016.08.008
          5132405
          27590114
          c033993a-0c66-4127-9dbb-c91a514e7bd6
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