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Cancer Immunology, Immunotherapy

, Volume 59, Issue 11, pp 1655–1663 | Cite as

Non-hematopoietic expression of IDO is integrally required for inflammatory tumor promotion

  • Alexander J. Muller
  • James B. DuHadaway
  • Mee Young Chang
  • Arivudinambi Ramalingam
  • Erika Sutanto-Ward
  • Janette Boulden
  • Alejandro P. Soler
  • Laura Mandik-Nayak
  • Susan K. Gilmour
  • George C. PrendergastEmail author
Original Article

Abstract

Indoleamine 2,3-dioxygenase (IDO) is generally considered to be immunosuppressive but recent findings suggest this characterization oversimplifies its role in disease pathogenesis. Recently, we showed that IDO is essential for tumor outgrowth in the classical two-stage model of inflammatory skin carcinogenesis. Here, we report that IDO loss did not exacerbate classical inflammatory responses. Rather, IDO induction could be elicited by environmental signals and tumor promoters as an integral component of the inflammatory tissue microenvironment even in the absence of cancer. IDO loss had limited impact on tumor outgrowth in carcinogenesis models that lacked an explicit inflammatory tumor promoter. In the context of inflammatory carcinogenesis where IDO was critical to tumor development, the most important source of IDO was radiation-resistant non-hematopoietic cells, consistent with evidence that loss of the IDO regulatory tumor suppressor gene Bin1 in transformed skin cells facilitates IDO-mediated immune escape by a cell autonomous mechanism. Taken together, our results identify IDO as an integral component of ‘cancer-associated’ inflammation that tilts the immune system toward tumor support. More generally, they promote the concept that mediators of immune escape and cancer-associated inflammation may be genetically synonymous.

Keywords

Indoleamine 2,3-dioxygenase Immunosuppression Carcinogenesis 

Notes

Acknowledgments

This work was supported by grants from the DoD Breast Cancer Research Program (A.J.M., G.C.P.), Pennsylvania Department of Health CURE/Tobacco Settlement Award (A.J.M.) and NIH grants CA82222 (G.C.P.), CA109542 (G.C.P.), and CA070739 (S.K.G.). Additional support was also provided by New Link Genetics Corporation, Dan Green Foundation, Lankenau Hospital Foundation, and the Main Line Health System (G.C.P.). A conflict of interest is declared by G.C.P., A.J.M., and J.B.D. who have intellectual property rights and financial interests in New Link Genetics Corporation which is developing IDO inhibitors for treatment of cancer and other diseases.

Supplementary material

262_2010_891_MOESM1_ESM.tif (5.8 mb)
Supplementary material (TIFF 5.81 MB)

References

  1. 1.
    Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539–545CrossRefPubMedGoogle Scholar
  2. 2.
    Peek RM, Mohla S, DuBois RN (2005) Inflammation in the genesis and perpetuation of cancer: summary and recommendations from a National Cancer Institute-sponsored meeting. Cancer Res 65:8583–8586CrossRefPubMedGoogle Scholar
  3. 3.
    Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860–867CrossRefPubMedGoogle Scholar
  4. 4.
    Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7(3):211–217CrossRefPubMedGoogle Scholar
  5. 5.
    Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21(2):137–148CrossRefPubMedGoogle Scholar
  6. 6.
    Gajewski TF (2007) Failure at the effector phase: immune barriers at the level of the melanoma tumor microenvironment. Clin Cancer Res 13(18 Pt 1):5256–5261CrossRefPubMedGoogle Scholar
  7. 7.
    Munn DH, Mellor AL (2006) The tumor-draining lymph node as an immune-privileged site. Immunol Rev 213:146–158CrossRefPubMedGoogle Scholar
  8. 8.
    Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ et al (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450(7171):903–907CrossRefPubMedGoogle Scholar
  9. 9.
    Sotomayor EM, Borrello I, Rattis FM, Cuenca AG, Abrams J, Staveley-O’Carroll K et al (2001) Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression. Blood 98(4):1070–1077CrossRefPubMedGoogle Scholar
  10. 10.
    Yu P, Rowley DA, Fu YX, Schreiber H (2006) The role of stroma in immune recognition and destruction of well-established solid tumors. Curr Opin Immunol 18(2):226–231CrossRefPubMedGoogle Scholar
  11. 11.
    Zhang B, Bowerman NA, Salama JK, Schmidt H, Spiotto MT, Schietinger A et al (2007) Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. J Exp Med 204(1):49–55CrossRefPubMedGoogle Scholar
  12. 12.
    Ball HJ, Sanchez-Perez A, Weiser S, Austin CJ, Astelbauer F, Miu J et al (2007) Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice. Gene 396(1):203–213CrossRefPubMedGoogle Scholar
  13. 13.
    Metz R, DuHadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC (2007) Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor IDO inhibitory compound D-1MT. Cancer Res 67:7082–7087CrossRefPubMedGoogle Scholar
  14. 14.
    Munn DH, Mellor AL (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 117(5):1147–1154CrossRefPubMedGoogle Scholar
  15. 15.
    Mellor AL, Sivakumar J, Chandler PKS, Molina H, Mao D et al (2001) Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy. Nat Immunol 2:64–68CrossRefPubMedGoogle Scholar
  16. 16.
    Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B et al (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281:1191–1193CrossRefPubMedGoogle Scholar
  17. 17.
    Muller AJ, DuHadaway JB, Sutanto-Ward E, Donover PS, Prendergast GC (2005) Inhibition of indoleamine 2,3-dioxygenase, an immunomodulatory target of the tumor suppressor gene Bin1, potentiates cancer chemotherapy. Nat Med 11:312–319CrossRefPubMedGoogle Scholar
  18. 18.
    Muller AJ, Prendergast GC (2007) Indoleamine 2,3-dioxygenase in immune suppression and cancer. Curr Cancer Drug Targets 7(1):31–40CrossRefPubMedGoogle Scholar
  19. 19.
    Muller AJ, Sharma MD, Chandler PR, Duhadaway JB, Everhart ME, Johnson BA III et al (2008) Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase. Proc Natl Acad Sci USA 105(44):17073–17078CrossRefPubMedGoogle Scholar
  20. 20.
    Chang M, Boulden J, Katz JB, Wang L, Meyer TJ, Soler AP et al (2007) Bin1 ablation increases susceptibility to cancer during aging, particularly lung cancer. Cancer Res 67:7605–7612CrossRefPubMedGoogle Scholar
  21. 21.
    Hardy RR, Carmack CE, Shinton SA, Kemp JD, Hayakawa K (1991) Resolution and characterization of pro-B and pre-B cell stages in normal mouse bone marrow. J Exp Med 173:1213–1225CrossRefPubMedGoogle Scholar
  22. 22.
    Chang M, Boulden J, Sutanto-Ward E, Duhadaway JB, Soler AP, Muller AJ et al (2007) Bin1 ablation in mammary gland delays tissue remodeling and drives cancer progression. Cancer Res 67:100–107CrossRefPubMedGoogle Scholar
  23. 23.
    Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M et al (2007) Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res 67(2):792–801CrossRefPubMedGoogle Scholar
  24. 24.
    Muller AJ, DuHadaway JB, Jaller D, Curtis P, Metz R, Prendergast GC (2010) Immunotherapeutic suppression of IDO and tumor growth by ethyl pyruvate. Cancer Res 70(5):1845–1853CrossRefPubMedGoogle Scholar
  25. 25.
    Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA et al (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27(1):68–73CrossRefPubMedGoogle Scholar
  26. 26.
    Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4(4):330–336CrossRefPubMedGoogle Scholar
  27. 27.
    Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP et al (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270(5238):985–988CrossRefPubMedGoogle Scholar
  28. 28.
    Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3(5):541–547CrossRefPubMedGoogle Scholar
  29. 29.
    Mellor AL, Baban B, Chandler P, Marshall B, Jhaver K, Hansen A et al (2003) Cutting edge: induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J Immunol 171(4):1652–1655PubMedGoogle Scholar
  30. 30.
    Robinson CM, Shirey KA, Carlin JM (2003) Synergistic transcriptional activation of indoleamine dioxygenase by IFN-gamma and tumor necrosis factor-alpha. J Interferon Cytokine Res 23(8):413–421CrossRefPubMedGoogle Scholar
  31. 31.
    Prendergast GC, Jaffee EM (2007) Cancer immunologists and cancer biologists: why we didn’t talk then but need to now. Cancer Res 67(8):3500–3504CrossRefPubMedGoogle Scholar
  32. 32.
    Brandacher G, Perathoner A, Ladurner R, Schneeberger S, Obrist P, Winkler C et al (2006) Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res 12(4):1144–1151CrossRefPubMedGoogle Scholar
  33. 33.
    Chamuleau ME, van de Loosdrecht AA, Hess CJ, Janssen JJ, Zevenbergen A, Delwel R et al (2008) High INDO (indoleamine 2,3-dioxygenase) mRNA level in blasts of acute myeloid leukemic patients predicts poor clinical outcome. Haematologica 93(12):1894–1898CrossRefPubMedGoogle Scholar
  34. 34.
    Ino K, Yoshida N, Kajiyama H, Shibata K, Yamamoto E, Kidokoro K et al (2006) Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer. Br J Cancer 95(11):1555–1561CrossRefPubMedGoogle Scholar
  35. 35.
    Okamoto A, Nikaido T, Ochiai K, Takakura S, Saito M, Aoki Y et al (2005) Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin Cancer Res 11(16):6030–6039CrossRefPubMedGoogle Scholar
  36. 36.
    Pan K, Wang H, Chen MS, Zhang HK, Weng DS, Zhou J et al (2008) Expression and prognosis role of indoleamine 2,3-dioxygenase in hepatocellular carcinoma. J Cancer Res Clin Oncol 134(11):1247–1253CrossRefPubMedGoogle Scholar
  37. 37.
    Urakawa H, Nishida Y, Nakashima H, Shimoyama Y, Nakamura S, Ishiguro N (2009). Prognostic value of indoleamine 2,3-dioxygenase expression in high grade osteosarcoma. Clin Exp Metastasis 26(8):1005–1012Google Scholar
  38. 38.
    Weinlich G, Murr C, Richardsen L, Winkler C, Fuchs D (2007) Decreased serum tryptophan concentration predicts poor prognosis in malignant melanoma patients. Dermatology 214(1):8–14CrossRefPubMedGoogle Scholar
  39. 39.
    Yoshikawa T, Hara T, Tsurumi H, Goto N, Hoshi M, Kitagawa J et al (2009) Serum concentration of L-kynurenine predicts the clinical outcome of patients with diffuse large B-cell lymphoma treated with R-CHOP. Eur J Haematol 84(4):304–309Google Scholar
  40. 40.
    Arefayene M, Philips S, Cao D, Mamidipalli S, Desta Z, Flockhart D et al (2009) Identification of genetic variants in the human indoleamine 2,3-dioxygenase (IDO1) gene, which have altered enzyme activity. Pharmactogenet Genomics 19:464–476CrossRefGoogle Scholar
  41. 41.
    Witkiewicz AK, Costantino CL, Metz R, Muller AJ, Prendergast GC, Yeo CJ et al (2009) Genotyping and expression analysis of IDO2 in human pancreatic cancer: a novel, active target. J Am Coll Surg 208(5):781–787 (discussion 7–9)CrossRefPubMedGoogle Scholar
  42. 42.
    Muller AJ, Scherle PA (2006) Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors. Nat Rev Cancer 6(8):613–625CrossRefPubMedGoogle Scholar
  43. 43.
    Griner EM, Kazanietz MG (2007) Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer 7(4):281–294CrossRefPubMedGoogle Scholar
  44. 44.
    Sayama S, Yoshida R, Oku T, Imanishi J, Kishida T, Hayaishi O (1981) Inhibition of interferon-mediated induction of indoleamine 2,3-dioxygenase in mouse lung by inhibitors of prostaglandin biosynthesis. Proc Natl Acad Sci USA 78(12):7327–7330CrossRefPubMedGoogle Scholar
  45. 45.
    Basu GD, Tinder TL, Bradley JM, Tu T, Hattrup CL, Pockaj BA et al (2006) Cyclooxygenase-2 inhibitor enhances the efficacy of a breast cancer vaccine: role of IDO. J Immunol 177(4):2391–2402PubMedGoogle Scholar
  46. 46.
    Lee SY, Choi HK, Lee KJ, Jung JY, Hur GY, Jung KH et al (2009) The immune tolerance of cancer is mediated by IDO that is inhibited by COX-2 inhibitors through regulatory T cells. J Immunother 32(1):22–28CrossRefPubMedGoogle Scholar
  47. 47.
    Munn DH, Sharma MD, Hou D, Baban B, Lee JR, Antonia SJ et al (2004) Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 114(2):280–290PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Alexander J. Muller
    • 1
    • 3
  • James B. DuHadaway
    • 1
  • Mee Young Chang
    • 1
  • Arivudinambi Ramalingam
    • 1
  • Erika Sutanto-Ward
    • 1
  • Janette Boulden
    • 1
  • Alejandro P. Soler
    • 1
    • 2
  • Laura Mandik-Nayak
    • 1
    • 4
  • Susan K. Gilmour
    • 1
    • 3
    • 5
  • George C. Prendergast
    • 1
    • 3
    • 5
    Email author
  1. 1.Lankenau Institute for Medical ResearchWynnewoodUSA
  2. 2.Richfield Laboratory of DermatopathologyCincinnatiUSA
  3. 3.Kimmel Cancer Center, Jefferson Medical CollegeThomas Jefferson UniversityPhiladelphiaUSA
  4. 4.Department of Microbiology and Immunology, Jefferson Medical CollegeThomas Jefferson UniversityPhiladelphiaUSA
  5. 5.Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical CollegeThomas Jefferson UniversityPhiladelphiaUSA

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