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

Nupur Bhattacharya, Robert Yuan, Tyler R. Prestwood, Hweixian Leong Penny, Michael A. DiMaio, Nathan E. Reticker-Flynn, Charles R. Krois, Justin A. Kenkel, Tho D. Pham, Yaron Carmi, Lorna Tolentino, Okmi Choi, Reyna Hulett, Jinshan Wang, Daniel A. Winer, Joseph L. Napoli, Edgar G. Engleman

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

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.

Original languageEnglish
Pages (from-to)641-655
Number of pages15
JournalImmunity
Volume45
Issue number3
DOIs
StatePublished - 20 Sep 2016
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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