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Therapeutic targeting of inflammation and tryptophan metabolism in colon and gastrointestinal cancer

Published:August 03, 2015DOI:https://doi.org/10.1016/j.trsl.2015.07.003
      Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer death in the United States. Cytotoxic therapies cause significant adverse effects for most patients and do not offer cure in many advanced cases of CRC. Immunotherapy is a promising new approach to harness the body's own immune system and inflammatory response to attack and clear the cancer. Tryptophan metabolism along the kynurenine pathway (KP) is a particularly promising target for immunotherapy. Indoleamine 2,3-dioxygenase 1 (IDO1) is the most well studied of the enzymes that initiate this pathway and it is commonly overexpressed in CRC. Herein, we provide an in-depth review of how tryptophan metabolism and KP metabolites shape factors important to CRC pathogenesis including the host mucosal immune system, pivotal transcriptional pathways of neoplastic growth, and luminal microbiota. This pathway's role in other gastrointestinal (GI) malignancies such as gastric, pancreatic, esophageal, and GI stromal tumors is also discussed. Finally, we highlight how currently available small molecule inhibitors and emerging methods for therapeutic targeting of IDO1 might be applied to colon, rectal, and colitis–associated cancer.

      Abbreviations:

      ACF (aberrant crypt foci), AHR (aryl hydrocarbon receptor), AOM (azoxymethane), APC (adenomatous polyposis coli), CAC (colitis-associated cancer), CD (cluster of differentiation), COX-2 (cyclooxygenase 2), CRC (colorectal cancer), DC (dendritic cell), DNA (deoxyribonucleic acid), GCN2 (general control nonderepressible 2), GSK-3β (glycogen synthase kinase 3 beta), IDO1 (indoleamine 2,3-dioxygenase 1), IDO2 (indoleamine 2,3-dioxygenase 2), IFN (interferon), IL (interleukin), iNOS (inducible nitric oxide synthase), KP (kynurenine pathway), KRAS (Kirsten rat sarcoma), 1 mT (1-methyltryptophan), mTOR (mammalian target of rapamycin), NF-κB (nuclear factor kappa B), NO (nitric oxide), PDA (pancreatic ductal adenocarcinoma), QPRT (quinolinate phosphoribosyltransferase), STAT (signal transducers and activators of transcription), TDO2 (tryptophan dioxygenase), TGF-β (transforming growth factor β), TLR (toll-like receptor), TNF (tumor necrosis factor), Tregs (regulatory T cells)
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      References

        • Grivennikov S.I.
        • Greten F.R.
        • Karin M.
        Immunity, inflammation, and cancer.
        Cell. 2010; 140: 883-899
        • Thaker A.I.
        • Rao M.S.
        • Bishnupuri K.S.
        • et al.
        IDO1 metabolites activate beta-catenin signaling to promote cancer cell proliferation and colon tumorigenesis in mice.
        Gastroenterology. 2013; 145 (e1–4): 416-425
        • Ferdinande L.
        • Decaestecker C.
        • Verset L.
        • et al.
        Clinicopathological significance of indoleamine 2,3-dioxygenase 1 expression in colorectal cancer.
        Br J Cancer. 2012; 106: 141-147
        • Ciorba M.A.
        Indoleamine 2,3 dioxygenase in intestinal disease.
        Curr Opin Gastroenterol. 2013; 29: 146-152
        • Beaugerie L.
        • Itzkowitz S.H.
        Cancers complicating inflammatory bowel disease.
        N Engl J Med. 2015; 372: 1441-1452
        • Prendergast G.C.
        • Smith C.
        • Thomas S.
        • et al.
        Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer.
        Cancer Immunol Immunother. 2014; 63: 721-735
        • Ferlay J.
        • Soerjomataram I.
        • Dikshit R.
        • et al.
        Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
        Int J Cancer. 2015; 136: E359-E386
        • Xiang B.
        • Snook A.E.
        • Magee M.S.
        • et al.
        Colorectal cancer immunotherapy.
        Discov Med. 2013; 15: 301-308
        • Terzic J.
        • Grivennikov S.
        • Karin E.
        • et al.
        Inflammation and colon cancer.
        Gastroenterology. 2010; 138: 2101-2114.e5
        • Ullman T.A.
        • Itzkowitz S.H.
        Intestinal inflammation and cancer.
        Gastroenterology. 2011; 140: 1807-1816
        • Abraham C.
        • Cho J.H.
        Inflammatory bowel disease.
        N Engl J Med. 2009; 361: 2066-2078
        • Eaden J.A.
        • Abrams K.R.
        • Mayberry J.F.
        The risk of colorectal cancer in ulcerative colitis: a meta-analysis.
        Gut. 2001; 48: 526-535
      1. Horner M.J. Ries L.A.G. Krapcho M. SEER Stat Fact Sheets—cancer of the colon and rectum. SEER cancer statistics review, 1975-2006, vol 2009. National Cancer Institute, Bethesda, MD2009 (based on November 2008 SEER data submission)
        • Low D.
        • Mino-Kenudson M.
        • Mizoguchi E.
        Recent advancement in understanding colitis-associated tumorigenesis.
        Inflamm Bowel Dis. 2014; 20: 2115-2123
        • Waldner M.J.
        • Neurath M.F.
        Mechanisms of immune signaling in colitis-associated cancer.
        Cell Mol Gastroenterol Hepatol. 2015; 1: 6-16
        • He T.C.
        • Sparks A.B.
        • Rago C.
        • et al.
        Identification of c-MYC as a target of the APC pathway.
        Science. 1998; 281: 1509-1512
        • Coca S.
        • Perez-Piqueras J.
        • Martinez D.
        • et al.
        The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma.
        Cancer. 1997; 79: 2320-2328
        • Pages F.
        • Berger A.
        • Camus M.
        • et al.
        Effector memory T cells, early metastasis, and survival in colorectal cancer.
        N Engl J Med. 2005; 353: 2654-2666
        • Galon J.
        • Costes A.
        • Sanchez-Cabo F.
        • et al.
        Type, density, and location of immune cells within human colorectal tumors predict clinical outcome.
        Science. 2006; 313: 1960-1964
        • Dunn G.P.
        • Bruce A.T.
        • Ikeda H.
        • et al.
        Cancer immunoediting: from immunosurveillance to tumor escape.
        Nat Immunol. 2002; 3: 991-998
        • Nan H.
        • Hutter C.M.
        • Lin Y.
        • et al.
        Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants.
        JAMA. 2015; 313: 1133-1142
        • Velayos F.S.
        • Loftus Jr., E.V.
        • Jess T.
        • et al.
        Predictive and protective factors associated with colorectal cancer in ulcerative colitis: a case-control study.
        Gastroenterology. 2006; 130: 1941-1949
        • Popivanova B.K.
        • Kitamura K.
        • Wu Y.
        • et al.
        Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis.
        J Clin Invest. 2008; 118: 560-570
        • Wang D.
        • DuBois R.N.
        Myeloid-derived suppressor cells link inflammation to cancer.
        Oncoimmunology. 2014; 3: e28581
        • Katoh H.
        • Wang D.
        • Daikoku T.
        • et al.
        CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis.
        Cancer Cell. 2013; 24: 631-644
        • Kanterman J.
        • Sade-Feldman M.
        • Biton M.
        • et al.
        Adverse immunoregulatory effects of 5FU and CPT11 chemotherapy on myeloid-derived suppressor cells and colorectal cancer outcomes.
        Cancer Res. 2014; 74: 6022-6035
        • Postow M.A.
        • Callahan M.K.
        • Barker C.A.
        • et al.
        Immunologic correlates of the abscopal effect in a patient with melanoma.
        N Engl J Med. 2012; 366: 925-931
        • Prendergast G.C.
        Cancer: why tumours eat tryptophan.
        Nature. 2011; 478: 192-194
        • Lob S.
        • Konigsrainer A.
        • Rammensee H.G.
        • et al.
        Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees?.
        Nat Rev Cancer. 2009; 9: 445-452
        • Platten M.
        • von Knebel Doeberitz N.
        • Oezen I.
        • et al.
        Cancer immunotherapy by targeting IDO1/TDO and their downstream effectors.
        Front Immunol. 2014; 5: 673
        • Peters J.C.
        Tryptophan nutrition and metabolism: an overview.
        Adv Exp Med Biol. 1991; 294: 345-358
        • Austin C.J.
        • Rendina L.M.
        Targeting key dioxygenases in tryptophan-kynurenine metabolism for immunomodulation and cancer chemotherapy.
        Drug Discov Today. 2015; 20: 609-617
        • Ball H.J.
        • Jusof F.F.
        • Bakmiwewa S.M.
        • et al.
        Tryptophan-catabolizing enzymes—party of three.
        Front Immunol. 2014; 5: 485
        • Opitz C.A.
        • Litzenburger U.M.
        • Sahm F.
        • et al.
        An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor.
        Nature. 2011; 478: 197-203
        • Pilotte L.
        • Larrieu P.
        • Stroobant V.
        • et al.
        Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase.
        Proc Natl Acad Sci U S A. 2012; 109: 2497-2502
        • Platten M.
        • Wick W.
        • Van den Eynde B.J.
        Tryptophan catabolism in cancer: beyond ido and tryptophan depletion.
        Cancer Res. 2012; 72: 5435-5440
        • Munn D.H.
        • Zhou M.
        • Attwood J.T.
        • et al.
        Prevention of allogeneic fetal rejection by tryptophan catabolism.
        Science. 1998; 281: 1191-1193
        • Munn D.H.
        • Shafizadeh E.
        • Attwood J.T.
        • et al.
        Inhibition of T cell proliferation by macrophage tryptophan catabolism.
        J Exp Med. 1999; 189: 1363-1372
        • Munn D.H.
        • Mellor A.L.
        Indoleamine 2,3-dioxygenase and tumor-induced tolerance.
        J Clin Invest. 2007; 117: 1147-1154
        • Fougeray S.
        • Mami I.
        • Bertho G.
        • et al.
        Tryptophan depletion and the kinase GCN2 mediate IFN-gamma-induced autophagy.
        J Immunol. 2012; 189: 2954-2964
        • Metz R.
        • Rust S.
        • Duhadaway J.B.
        • et al.
        IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: a novel IDO effector pathway targeted by D-1-methyl-tryptophan.
        Oncoimmunology. 2012; 1: 1460-1468
        • Mezrich J.D.
        • Fechner J.H.
        • Zhang X.
        • et al.
        An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells.
        J Immunol. 2010; 185: 3190-3198
        • Nguyen N.T.
        • Kimura A.
        • Nakahama T.
        • et al.
        Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism.
        Proc Natl Acad Sci U S A. 2010; 107: 19961-19966
        • DiNatale B.C.
        • Murray I.A.
        • Schroeder J.C.
        • et al.
        Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling.
        Toxicol Sci. 2010; 115: 89-97
        • Pallotta M.T.
        • Orabona C.
        • Volpi C.
        • et al.
        Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells.
        Nat Immunol. 2011; 12: 870-878
        • Zaher S.S.
        • Germain C.
        • Fu H.
        • et al.
        3-Hydroxykynurenine suppresses CD4+ T-cell proliferation, induces T-regulatory-cell development, and prolongs corneal allograft survival.
        Invest Ophthalmol Vis Sci. 2011; 52: 2640-2648
        • Romani L.
        • Puccetti P.
        Controlling pathogenic inflammation to fungi.
        Expert Rev Anti Infect Ther. 2007; 5: 1007-1017
        • Cobbold S.P.
        • Adams E.
        • Farquhar C.A.
        • et al.
        Infectious tolerance via the consumption of essential amino acids and mTOR signaling.
        Proc Natl Acad Sci U S A. 2009; 106: 12055-12060
        • Howie D.
        • Waldmann H.
        • Cobbold S.
        Nutrient sensing via mTOR in T cells maintains a tolerogenic microenvironment.
        Front Immunol. 2014; 5: 409
        • Pallotta M.T.
        • Fallarino F.
        • Matino D.
        • et al.
        AhR-mediated, non-genomic modulation of IDO1 function.
        Front Immunol. 2014; 5: 497
        • Bessede A.
        • Gargaro M.
        • Pallotta M.T.
        • et al.
        Aryl hydrocarbon receptor control of a disease tolerance defence pathway.
        Nature. 2014; 511: 184-190
        • Lee A.
        • Kanuri N.
        • Zhang Y.
        • et al.
        IDO1 and IDO2 non-synonymous gene variants: correlation with Crohn's disease risk and clinical phenotype.
        PLoS One. 2014; 9: e115848
        • Gurtner G.J.
        • Newberry R.D.
        • Schloemann S.R.
        • et al.
        Inhibition of indoleamine 2,3-dioxygenase augments trinitrobenzene sulfonic acid colitis in mice.
        Gastroenterology. 2003; 125: 1762-1773
        • Matteoli G.
        • Mazzini E.
        • Iliev I.D.
        • et al.
        Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction.
        Gut. 2010; 59: 595-604
        • Ciorba M.A.
        • Bettonville E.E.
        • McDonald K.G.
        • et al.
        Induction of IDO-1 by immunostimulatory DNA limits severity of experimental colitis.
        J Immunol. 2010; 184: 3907-3916
        • Gupta N.K.
        • Thaker A.I.
        • Kanuri N.
        • et al.
        Serum analysis of tryptophan catabolism pathway: correlation with Crohn's disease activity.
        Inflamm Bowel Dis. 2012; 18: 1214-1220
        • Kraus S.
        • Arber N.
        Inflammation and colorectal cancer.
        Curr Opin Pharmacol. 2009; 9: 405-410
        • Zou W.
        Immunosuppressive networks in the tumour environment and their therapeutic relevance.
        Nat Rev Cancer. 2005; 5: 263-274
        • Friberg M.
        • Jennings R.
        • Alsarraj M.
        • et al.
        Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection.
        Int J Cancer. 2002; 101: 151-155
        • Munn D.H.
        • Sharma M.D.
        • Lee J.R.
        • et al.
        Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase.
        Science. 2002; 297: 1867-1870
        • von Bergwelt-Baildon M.S.
        • Popov A.
        • Saric T.
        • et al.
        CD25 and indoleamine 2,3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibition.
        Blood. 2006; 108: 228-237
        • Watkins S.K.
        • Zhu Z.
        • Riboldi E.
        • et al.
        FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer.
        J Clin Invest. 2011; 121: 1361-1372
        • Curiel T.J.
        • Coukos G.
        • Zou L.
        • et al.
        Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.
        Nat Med. 2004; 10: 942-949
        • Grohmann U.
        • Orabona C.
        • Fallarino F.
        • et al.
        CTLA-4-Ig regulates tryptophan catabolism in vivo.
        Nat Immunol. 2002; 3: 1097-1101
        • Uyttenhove C.
        • Pilotte L.
        • Theate I.
        • et al.
        Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase.
        Nat Med. 2003; 9: 1269-1274
        • Muller A.J.
        • DuHadaway J.B.
        • Donover P.S.
        • et al.
        Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy.
        Nat Med. 2005; 11: 312-319
        • Hou D.Y.
        • Muller A.J.
        • Sharma M.D.
        • et al.
        Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses.
        Cancer Res. 2007; 67: 792-801
        • Theate I.
        • van Baren N.
        • Pilotte L.
        • et al.
        Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues.
        Cancer Immunol Res. 2015; 3: 161-172
        • Prendergast G.C.
        Immune escape as a fundamental trait of cancer: focus on IDO.
        Oncogene. 2008; 27: 3889-3900
        • Liu X.
        • Shin N.
        • Koblish H.K.
        • et al.
        Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity.
        Blood. 2010; 115: 3520-3530
        • Walczak K.
        • Dabrowski W.
        • Langner E.
        • et al.
        Kynurenic acid synthesis and kynurenine aminotransferases expression in colon derived normal and cancer cells.
        Scand J Gastroenterol. 2011; 46: 903-912
        • Engin A.B.
        • Karahalil B.
        • Karakaya A.E.
        • et al.
        Helicobacter pylori and serum kynurenine-tryptophan ratio in patients with colorectal cancer.
        World J Gastroenterol. 2015; 21: 3636-3643
        • Brandacher G.
        • Perathoner A.
        • Ladurner R.
        • et al.
        Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells.
        Clin Cancer Res. 2006; 12: 1144-1151
        • Gao Y.F.
        • Peng R.Q.
        • Li J.
        • et al.
        The paradoxical patterns of expression of indoleamine 2,3-dioxygenase in colon cancer.
        J Transl Med. 2009; 7: 71
        • Ogawa K.
        • Hara T.
        • Shimizu M.
        • et al.
        Suppression of azoxymethane-induced colonic preneoplastic lesions in rats by 1-methyltryptophan, an inhibitor of indoleamine 2,3-dioxygenase.
        Cancer Sci. 2012; 103: 951-958
        • Takahashi M.
        • Wakabayashi K.
        Gene mutations and altered gene expression in azoxymethane-induced colon carcinogenesis in rodents.
        Cancer Sci. 2004; 95: 475-480
        • Smith C.
        • Chang M.Y.
        • Parker K.H.
        • et al.
        IDO is a nodal pathogenic driver of lung cancer and metastasis development.
        Cancer Discov. 2012; 2: 722-735
        • Lob S.
        • Konigsrainer A.
        • Zieker D.
        • et al.
        IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism.
        Cancer Immunol Immunother. 2009; 58: 153-157
        • Flatmark K.
        • Maelandsmo G.M.
        • Martinsen M.
        • et al.
        Twelve colorectal cancer cell lines exhibit highly variable growth and metastatic capacities in an orthotopic model in nude mice.
        Eur J Cancer. 2004; 40: 1593-1598
        • Ahmed D.
        • Eide P.W.
        • Eilertsen I.A.
        • et al.
        Epigenetic and genetic features of 24 colon cancer cell lines.
        Oncogenesis. 2013; 2: e71
        • Smith G.
        • Carey F.A.
        • Beattie J.
        • et al.
        Mutations in APC, Kirsten-ras, and p53–alternative genetic pathways to colorectal cancer.
        Proc Natl Acad Sci U S A. 2002; 99: 9433-9438
        • Wong G.S.
        • Lee J.S.
        • Park Y.Y.
        • et al.
        Periostin cooperates with mutant p53 to mediate invasion through the induction of STAT1 signaling in the esophageal tumor microenvironment.
        Oncogenesis. 2013; 2: e59
        • Chon S.Y.
        • Hassanain H.H.
        • Gupta S.L.
        Cooperative role of interferon regulatory factor 1 and p91 (STAT1) response elements in interferon-gamma-inducible expression of human indoleamine 2,3-dioxygenase gene.
        J Biol Chem. 1996; 271: 17247-17252
        • Litzenburger U.M.
        • Opitz C.A.
        • Sahm F.
        • et al.
        Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR.
        Oncotarget. 2014; 5: 1038-1051
        • Ciorba M.A.
        A gastroenterologist's guide to probiotics.
        Clin Gastroenterol Hepatol. 2012; 10: 960-968
        • Arthur J.C.
        • Gharaibeh R.Z.
        • Muhlbauer M.
        • et al.
        Microbial genomic analysis reveals the essential role of inflammation in bacteria-induced colorectal cancer.
        Nat Commun. 2014; 5: 4724
        • Wells J.M.
        • Rossi O.
        • Meijerink M.
        • et al.
        Epithelial crosstalk at the microbiota-mucosal interface.
        Proc Natl Acad Sci U S A. 2011; 108: 4607-4614
        • Zelante T.
        • Iannitti R.G.
        • Cunha C.
        • et al.
        Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22.
        Immunity. 2013; 39: 372-385
        • Sommariva M.
        • De Cecco L.
        • De Cesare M.
        • et al.
        TLR9 agonists oppositely modulate DNA repair genes in tumor versus immune cells and enhance chemotherapy effects.
        Cancer Res. 2011; 71: 6382-6390
        • Fallarino F.
        • Pallotta M.T.
        • Matino D.
        • et al.
        LPS-conditioned dendritic cells confer endotoxin tolerance contingent on tryptophan catabolism.
        Immunobiology. 2015; 220: 315-321
        • Hoshi M.
        • Osawa Y.
        • Ito H.
        • et al.
        Blockade of indoleamine 2,3-dioxygenase reduces mortality from peritonitis and sepsis in mice by regulating functions of CD11b+ peritoneal cells.
        Infect Immun. 2014; 82: 4487-4495
        • Eiro N.
        • Gonzalez L.
        • Gonzalez L.O.
        • et al.
        Study of the expression of toll-like receptors in different histological types of colorectal polyps and their relationship with colorectal cancer.
        J Clin Immunol. 2012; 32: 848-854
        • Iida N.
        • Dzutsev A.
        • Stewart C.A.
        • et al.
        Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment.
        Science. 2013; 342: 967-970
        • Furi I.
        • Sipos F.
        • Germann T.M.
        • et al.
        Epithelial toll-like receptor 9 signaling in colorectal inflammation and cancer: clinico-pathogenic aspects.
        World J Gastroenterol. 2013; 19: 4119-4126
        • Ito H.
        • Ando T.
        • Arioka Y.
        • Saito K.
        • Seishima M.
        Inhibition of indoleamine 2,3-dioxygenase activity enhances the anti-tumor effects of a TLR7 agonist in an established cancer model.
        Immunology. 2015; 144: 621-630
        • Sommariva M.
        • De Cecco L.
        • Tagliabue E.
        • et al.
        Modulation of DNA repair genes induced by TLR9 agonists: a strategy to eliminate “altered” cells?.
        Oncoimmunology. 2012; 1: 258-259
        • Nugent J.L.
        • McCoy A.N.
        • Addamo C.J.
        • et al.
        Altered tissue metabolites correlate with microbial dysbiosis in colorectal adenomas.
        J Proteome Res. 2014; 13: 1921-1929
        • Chen W.
        • Liu F.
        • Ling Z.
        • et al.
        Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer.
        PLoS One. 2012; 7: e39743
        • Weir T.L.
        • Manter D.K.
        • Sheflin A.M.
        • et al.
        Stool microbiome and metabolome differences between colorectal cancer patients and healthy adults.
        PLoS One. 2013; 8: e70803
        • Raman M.
        • Ambalam P.
        • Kondepudi K.K.
        • et al.
        Potential of probiotics, prebiotics and synbiotics for management of colorectal cancer.
        Gut Microbes. 2013; 4: 181-192
        • He Y.W.
        • Wang H.S.
        • Zeng J.
        • et al.
        Sodium butyrate inhibits interferon-gamma induced indoleamine 2,3-dioxygenase expression via STAT1 in nasopharyngeal carcinoma cells.
        Life Sci. 2013; 93: 509-515
        • Wong J.M.
        • de Souza R.
        • Kendall C.W.
        • et al.
        Colonic health: fermentation and short chain fatty acids.
        J Clin Gastroenterol. 2006; 40: 235-243
        • Jiang G.M.
        • He Y.W.
        • Fang R.
        • et al.
        Sodium butyrate down-regulation of indoleamine 2,3-dioxygenase at the transcriptional and post-transcriptional levels.
        Int J Biochem Cell Biol. 2010; 42: 1840-1846
        • Singh N.
        • Gurav A.
        • Sivaprakasam S.
        • et al.
        Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis.
        Immunity. 2014; 40: 128-139
        • Wu N.
        • Yang X.
        • Zhang R.
        • et al.
        Dysbiosis signature of fecal microbiota in colorectal cancer patients.
        Microb Ecol. 2013; 66: 462-470
        • Kawajiri K.
        • Kobayashi Y.
        • Ohtake F.
        • et al.
        Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in ApcMin/+ mice with natural ligands.
        Proc Natl Acad Sci U S A. 2009; 106: 13481-13486
        • Biedermann L.
        • Rogler G.
        The intestinal microbiota: its role in health and disease.
        Eur J Pediatr. 2015; 174: 151-167
        • Murray I.A.
        • Patterson A.D.
        • Perdew G.H.
        Aryl hydrocarbon receptor ligands in cancer: friend and foe.
        Nat Rev Cancer. 2014; 14: 801-814
        • Andersson P.
        • McGuire J.
        • Rubio C.
        • et al.
        A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors.
        Proc Natl Acad Sci U S A. 2002; 99: 9990-9995
        • Gramatzki D.
        • Pantazis G.
        • Schittenhelm J.
        • et al.
        Aryl hydrocarbon receptor inhibition downregulates the TGF-beta/Smad pathway in human glioblastoma cells.
        Oncogene. 2009; 28: 2593-2605
        • Bertazzi P.A.
        • Consonni D.
        • Bachetti S.
        • et al.
        Health effects of dioxin exposure: a 20-year mortality study.
        Am J Epidemiol. 2001; 153: 1031-1044
        • Xie G.
        • Peng Z.
        • Raufman J.P.
        Src-mediated aryl hydrocarbon and epidermal growth factor receptor cross talk stimulates colon cancer cell proliferation.
        Am J Physiol Gastrointest Liver Physiol. 2012; 302: G1006-G1015
        • Safe S.
        • Lee S.O.
        • Jin U.H.
        Role of the aryl hydrocarbon receptor in carcinogenesis and potential as a drug target.
        Toxicol Sci. 2013; 135: 1-16
        • Garten A.
        • Petzold S.
        • Korner A.
        • et al.
        Nampt: linking NAD biology, metabolism and cancer.
        Trends Endocrinol Metab. 2009; 20: 130-138
        • Sahm F.
        • Oezen I.
        • Opitz C.A.
        • et al.
        The endogenous tryptophan metabolite and NAD+ precursor quinolinic acid confers resistance of gliomas to oxidative stress.
        Cancer Res. 2013; 73: 3225-3234
        • Xiao X.
        • Wang L.
        • Wei P.
        • et al.
        Role of MUC20 overexpression as a predictor of recurrence and poor outcome in colorectal cancer.
        J Transl Med. 2013; 11: 151
        • Kawamori T.
        • Uchiya N.
        • Sugimura T.
        • et al.
        Enhancement of colon carcinogenesis by prostaglandin E2 administration.
        Carcinogenesis. 2003; 24: 985-990
        • Markowitz S.D.
        • Bertagnolli M.M.
        Molecular origins of cancer: molecular basis of colorectal cancer.
        N Engl J Med. 2009; 361: 2449-2460
        • Cianchi F.
        • Cortesini C.
        • Fantappie O.
        • et al.
        Inducible nitric oxide synthase expression in human colorectal cancer: correlation with tumor angiogenesis.
        Am J Pathol. 2003; 162: 793-801
        • Takahashi M.
        • Mutoh M.
        • Kawamori T.
        • et al.
        Altered expression of beta-catenin, inducible nitric oxide synthase and cyclooxygenase-2 in azoxymethane-induced rat colon carcinogenesis.
        Carcinogenesis. 2000; 21: 1319-1327
        • Hao X.P.
        • Pretlow T.G.
        • Rao J.S.
        • et al.
        Inducible nitric oxide synthase (iNOS) is expressed similarly in multiple aberrant crypt foci and colorectal tumors from the same patients.
        Cancer Res. 2001; 61: 419-422
        • Mei J.M.
        • Hord N.G.
        • Winterstein D.F.
        • et al.
        Expression of prostaglandin endoperoxide H synthase-2 induced by nitric oxide in conditionally immortalized murine colonic epithelial cells.
        FASEB J. 2000; 14: 1188-1201
        • Zhu Y.
        • Zhu M.
        • Lance P.
        iNOS signaling interacts with COX-2 pathway in colonic fibroblasts.
        Exp Cell Res. 2012; 318: 2116-2127
        • Marnett L.J.
        • Wright T.L.
        • Crews B.C.
        • et al.
        Regulation of prostaglandin biosynthesis by nitric oxide is revealed by targeted deletion of inducible nitric-oxide synthase.
        J Biol Chem. 2000; 275: 13427-13430
        • Salvemini D.
        • Misko T.P.
        • Masferrer J.L.
        • et al.
        Nitric oxide activates cyclooxygenase enzymes.
        Proc Natl Acad Sci U S A. 1993; 90: 7240-7244
        • Salvemini D.
        • Riley D.P.
        • Lennon P.J.
        • et al.
        Protective effects of a superoxide dismutase mimetic and peroxynitrite decomposition catalysts in endotoxin-induced intestinal damage.
        Br J Pharmacol. 1999; 127: 685-692
        • Gobel C.
        • Breitenbuecher F.
        • Kalkavan H.
        • et al.
        Functional expression cloning identifies COX-2 as a suppressor of antigen-specific cancer immunity.
        Cell Death Dis. 2014; 5: e1568
        • Lee S.Y.
        • Choi H.K.
        • Lee K.J.
        • et al.
        The immune tolerance of cancer is mediated by IDO that is inhibited by COX-2 inhibitors through regulatory T cells.
        J Immunother. 2009; 32: 22-28
        • Iachininoto M.G.
        • Nuzzolo E.R.
        • Bonanno G.
        • et al.
        Cyclooxygenase-2 (COX-2) inhibition constrains indoleamine 2,3-dioxygenase 1 (IDO1) activity in acute myeloid leukaemia cells.
        Molecules. 2013; 18: 10132-10145
        • Zhang R.
        • Liu H.
        • Li F.
        • et al.
        The correlation between the subsets of tumor infiltrating memory T cells and the expression of indoleamine 2,3-dioxygenase in gastric cancer.
        Dig Dis Sci. 2013; 58: 3494-3502
        • Yoshii M.
        • Tanaka H.
        • Ohira M.
        • et al.
        Expression of Forkhead box P3 in tumour cells causes immunoregulatory function of signet ring cell carcinoma of the stomach.
        Br J Cancer. 2012; 106: 1668-1674
        • Zhang R.
        • Li H.
        • Yu J.
        • et al.
        Immunoactivative role of indoleamine 2,3dioxygenase in gastric cancer cells in vitro.
        Mol Med Rep. 2011; 4: 169-173
        • Witkiewicz A.
        • Williams T.K.
        • Cozzitorto J.
        • et al.
        Expression of indoleamine 2,3-dioxygenase in metastatic pancreatic ductal adenocarcinoma recruits regulatory T cells to avoid immune detection.
        J Am Coll Surg. 2008; 206 (discussion 854–6): 849-854
        • Witkiewicz A.K.
        • Costantino C.L.
        • Metz R.
        • et al.
        Genotyping and expression analysis of IDO2 in human pancreatic cancer: a novel, active target.
        J Am Coll Surg. 2009; 208 (discussion 787–9): 781-787
        • Koblish H.K.
        • Hansbury M.J.
        • Bowman K.J.
        • et al.
        Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors.
        Mol Cancer Ther. 2010; 9: 489-498
        • Liu J.
        • Lu G.
        • Tang F.
        • et al.
        Localization of indoleamine 2,3-dioxygenase in human esophageal squamous cell carcinomas.
        Virchows Arch. 2009; 455: 441-448
        • Zhang G.
        • Liu W.L.
        • Zhang L.
        • et al.
        Involvement of indoleamine 2,3-dioxygenase in impairing tumor-infiltrating CD8 T-cell functions in esophageal squamous cell carcinoma.
        Clin Dev Immunol. 2011; 2011: 384726
        • Balachandran V.P.
        • Cavnar M.J.
        • Zeng S.
        • et al.
        Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido.
        Nat Med. 2011; 17: 1094-1100
        • Metz R.
        • Duhadaway J.B.
        • Kamasani U.
        • et al.
        Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan.
        Cancer Res. 2007; 67: 7082-7087
        • Metz R.
        • Smith C.
        • DuHadaway J.B.
        • et al.
        IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation.
        Int Immunol. 2014; 26: 357-367
        • Newton R.C.
        • Scherle P.A.
        • Bowman K.
        • et al.
        Pharmacodynamic assessment of INCB024360, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), in advanced cancer patients.
        J Clin Oncol. 2012; 30 (Abstract 2500)
        • Beatty G.L.
        • O'Dwyer P.J.
        • Clark J.
        • et al.
        Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the oral inhibitor of indoleamine 2,3-dioxygenase (IDO1) INCB024360 in patients (pts) with advanced malignancies.
        J Clin Oncol. 2013; 31 (suppl; abstract 3025)
        • Gao J.
        • Aksoy B.A.
        • Dogrusoz U.
        • et al.
        Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.
        Sci Signal. 2013; 6: pl1
        • Cerami E.
        • Gao J.
        • Dogrusoz U.
        • et al.
        The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.
        Cancer Discov. 2012; 2: 401-404
        • Puccetti P.
        • Fallarino F.
        • Italiano A.
        • et al.
        Accumulation of an endogenous tryptophan-derived metabolite in colorectal and breast cancers.
        PLoS One. 2015; 10: e0122046
        • Zheng X.
        • Koropatnick J.
        • Li M.
        • et al.
        Reinstalling antitumor immunity by inhibiting tumor-derived immunosuppressive molecule IDO through RNA interference.
        J Immunol. 2006; 177: 5639-5646
        • Zheng X.
        • Koropatnick J.
        • Chen D.
        • et al.
        Silencing IDO in dendritic cells: a novel approach to enhance cancer immunotherapy in a murine breast cancer model.
        Int J Cancer. 2013; 132: 967-977
        • Maleki Vareki S.
        • Rytelewski M.
        • Figueredo R.
        • et al.
        Indoleamine 2,3-dioxygenase mediates immune-independent human tumor cell resistance to olaparib, gamma radiation, and cisplatin.
        Oncotarget. 2014; 5: 2778-2791
        • Le D.T.
        • Uram J.N.
        • Wang H.
        • et al.
        PD-1 blockade in tumors with mismatch-repair deficiency.
        N Engl J Med. 2015; 372: 2509-2520