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

• Published in: Immunity (Cambridge, Mass.) Vol. 45; no. 3; pp. 641 - 655
• Main Authors: Bhattacharya, Nupur, Yuan, Robert, Prestwood, Tyler R., Penny, Hweixian Leong, DiMaio, Michael A., Reticker-Flynn, Nathan E., Krois, Charles R., Kenkel, Justin A., Pham, Tho D., Carmi, Yaron, Tolentino, Lorna, Choi, Okmi, Hulett, Reyna, Wang, Jinshan, Winer, Daniel A., Napoli, Joseph L., Engleman, Edgar G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-09-2016; Elsevier Limited
• Subjects: Animals; Carcinogenesis - immunology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Colon - immunology; Colon - metabolism; Colorectal cancer; Colorectal Neoplasms - immunology; Colorectal Neoplasms - metabolism; Enzymes; Female; Flow cytometry; Histology; Humans; Immunoglobulins; Inflammation; Inflammatory bowel disease; Lymphocytes; Mass spectrometry; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Microbiota - immunology; Mortality; Protein expression; Retinoic Acid 4-Hydroxylase - metabolism; Rodents; Scientific imaging; Signal Transduction - immunology; Software; Studies; Tretinoin - metabolism; Up-Regulation - immunology
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.08.008

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.
[Display omitted]
•atRA deficiency in colon cancer is driven by microbiota-induced inflammation•Treatment with atRA reduces tumorigenesis by enhancing a CD8+ T cell response•The enhanced CD8+ T cell response is due to upregulation of MHCI on tumor cells•CD8+ T cell cytotoxicity in human colon cancer correlates with local atRA metabolism
All-trans-retinoic acid (atRA) plays crucial roles in shaping intestinal immunity. Bhattacharya et al. show that, in the context of colon cancer, microbiota-induced intestinal inflammation alters atRA metabolism, leading to a colonic atRA deficit and exacerbation of colon carcinogenesis. atRA supplementation ameliorates colon carcinogenesis in a CD8+ T cell-dependent manner.