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IDO expression in breast cancer: an assessment of 281 primary and metastatic cases with comparison to PD-L1

Modern Pathologyvolume 31pages15131522 (2018) | Download Citation


The immune inhibitory enzyme indoleamine 2,3-dioxygenase (IDO) has been associated with immune evasion in numerous malignancies and may mark these cancers as susceptible to anti-IDO therapies. We herein address IDO expression in breast cancers, examine the relationship between IDO and PD-L1, and investigate IDO fidelity across breast cancer primaries and metastases. IDO and PD-L1 expression was assessed in tissue microarrays containing 242 invasive primary breast cancers, 20 nodal metastases, and 19 distant metastases. IDO and PD-L1 were scored by extent in the tumor cells and immune infiltrate. Tumor IDO staining was seen in 14% of primaries including 38% of triple-negative cancers. IDO immune cell staining was seen in 14% of primaries and 29% of triple-negative cancers. Tumoral IDO and PD-L1 co-expression was seen in 8% of primaries, including 70% of tumoral PD-L1-positive cases. Immune IDO and PD-L1 co-expression was identified in 14% of primaries, including 48% of immune PD-L1-positive cases. Tumoral and immune cell IDO was conserved in 94% of matched primary/metastasis. In summary, IDO expression is common among high-grade, triple-negative breast cancers and is frequently associated with PD-L1 co-expression, suggesting that IDO might be a mechanism of anti-PD-1/PD-L1 immunotherapy resistance and that dual therapy may be of utility. Tumoral and immune cell IDO expression shows fidelity between primary and metastatic sites in treatment-naïve cancers, arguing against IDO as an independent driver for metastatic spread. Clinical trials are needed to assess the efficacy of IDO inhibition relative to IDO expression, as well as its possible role in combination with anti-PD-1/PD-L1 immunotherapy.

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  1. 1.

    Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27:111–22.

  2. 2.

    Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800.

  3. 3.

    Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.

  4. 4.

    Becht E, Giraldo NA, Germain C, et al. Immune contexture, immunoscore, and malignant cell molecular subgroups for prognostic and theranostic classifications of cancers. Adv Immunol. 2016;130:95–190.

  5. 5.

    Ali HR, Provenzano E, Dawson SJ, et al. Association between CD8 + T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol. 2014;25:1536–43.

  6. 6.

    Park JJ, Omiya R, Matsumura Y, et al. B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood. 2010;116:1291–8.

  7. 7.

    Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.

  8. 8.

    Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568–71.

  9. 9.

    Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci Usa. 2002;99:12293–7.

  10. 10.

    Hughes PE, Caenepeel S, Wu LC. Targeted therapy and checkpoint immunotherapy combinations for the treatment of cancer. Trends Immunol. 2016;37:462–76.

  11. 11.

    Wang X, Teng F, Kong L, Yu J. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther. 2016;9:5023–39.

  12. 12.

    Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8:467–77.

  13. 13.

    Reiss KA, Forde PM, Brahmer JR. Harnessing the power of the immune system via blockade of PD-1 and PD-L1: A promising new anticancer strategy. Immunotherapy. 2014;6:459–75.

  14. 14.

    Cimino-Mathews A, Thompson E, Taube JM, et al. PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas. Hum Pathol. 2016;47:52–63.

  15. 15.

    Engel JB, Honig A, Kapp M, et al. Mechanisms of tumor immune escape in triple-negative breast cancers (TNBC) with and without mutated BRCA 1. Arch Gynecol Obstet. 2014;289:141–7.

  16. 16.

    Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2:361–70.

  17. 17.

    Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase ib KEYNOTE-012 study. J Clin Oncol. 2016;34:2460–7.

  18. 18.

    Wang M, Zhang C, Song Y, et al. Mechanism of immune evasion in breast cancer. Onco Targets Ther. 2017;10:1561–73.

  19. 19.

    Chawla A, Philips AV, Alatrash G, Mittendorf E. Immune checkpoints: a therapeutic target in triple negative breast cancer. Oncoimmunology. 2014;3:e28325.

  20. 20.

    Dill EA, Gru AA, Atkins KA, et al. PD-L1 expression and intratumoral heterogeneity across breast cancer subtypes and stages: an assessment of 245 primary and 40 metastatic tumors. Am J Surg Pathol. 2017;41:334–42.

  21. 21.

    Munn DH, Mellor AL. IDO in the tumor microenvironment: Inflammation, counter-regulation, and tolerance. Trends Immunol. 2016;37:193–207.

  22. 22.

    Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 2013;34:137–43.

  23. 23.

    Moon YW, Hajjar J, Hwu P, Naing A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J Immunother Cancer. 2015;3:51–015-0094-9. eCollection 2015

  24. 24.

    Isla Larrain MT, Rabassa ME, Lacunza E, et al. IDO is highly expressed in breast cancer and breast cancer-derived circulating microvesicles and associated to aggressive types of tumors by in silico analysis. Tumour Biol. 2014;35:6511–9.

  25. 25.

    Soliman H, Rawal B, Fulp J, et al. Analysis of indoleamine 2-3 dioxygenase (IDO1) expression in breast cancer tissue by immunohistochemistry. Cancer Immunol Immunother. 2013;62:829–37.

  26. 26.

    Kim S, Park S, Cho MS, Lim W, Moon BI, Sung SH. Strong correlation of indoleamine 2,3-dioxygenase 1 expression with basal-like phenotype and increased lymphocytic infiltration in triple-negative breast cancer. J Cancer. 2017;8:124–30.

  27. 27.

    Jochems C, Fantini M, Fernando RI, et al. The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells. Oncotarget. 2016;7:37762–72.

  28. 28.

    Blocking IDO1 helps shrink bladder, cervical tumors. Cancer Discov. 2018;8:OF3.

  29. 29.

    Nayak A, Hao Z, Sadek R, Dobbins R, Marshall L, et al. Phase 1a study of the safety, pharmacokinetics, and pharmacodynamics of GDC-0919 in patients with recurrent/advanced solid tumors. Eur J Cancer. 2015;51:S69.

  30. 30.

    Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20:5064–74.

  31. 31.

    Mills AM, Dill EA, Moskaluk CA, Dziegielewski J, Bullock TN, Dillon PM. The relationship between mismatch repair deficiency and PD-L1 expression in breast carcinoma. Am J Surg Pathol. 2017;42:183–91.

  32. 32.

    Friedman K, Brodsky AS, Lu S, et al. Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment. Mod Pathol. 2016;29:528–41.

  33. 33.

    Iversen TZ, Andersen MH, Svane IM. The targeting of indoleamine 2,3 dioxygenase-mediated immune escape in cancer. Basic Clin Pharmacol Toxicol. 2015;116:19–24.

  34. 34.

    Schalper KA, Carvajal-Hausdorf D, McLaughlin J, et al. Differential expression and significance of PD-L1, IDO-1, and B7-H4 in human lung cancer. Clin Cancer Res. 2017;23:370–8.

  35. 35.

    Sordillo PP, Sordillo LA, Helson L. The kynurenine pathway: a primary resistance mechanism in patients with glioblastoma. Anticancer Res. 2017;37:2159–71.

  36. 36.

    Munn DH, Zhou M, Attwood JT, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281:1191–3.

  37. 37.

    Mellor AL, Baban B, Chandler P, et al. Cutting edge: Induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J Immunol. 2003;171:1652–5.

  38. 38.

    Szanto S, Koreny T, Mikecz K, Glant TT, Szekanecz Z, Varga J. Inhibition of indoleamine 2,3-dioxygenase-mediated tryptophan catabolism accelerates collagen-induced arthritis in mice. Arthritis Res Ther. 2007;9:R50.

  39. 39.

    Gurtner GJ, Newberry RD, Schloemann SR, McDonald KG, Stenson WF. Inhibition of indoleamine 2,3-dioxygenase augments trinitrobenzene sulfonic acid colitis in mice. Gastroenterology. 2003;125:1762–73.

  40. 40.

    Fallarino F, Volpi C, Zelante T, et al. IDO mediates TLR9-driven protection from experimental autoimmune diabetes. J Immunol. 2009;183:6303–12.

  41. 41.

    Yan Y, Zhang GX, Gran B, et al. IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. J Immunol. 2010;185:5953–61.

  42. 42.

    Heng B, Lim CK, Lovejoy DB, Bessede A, Gluch L, Guillemin GJ. Understanding the role of the kynurenine pathway in human breast cancer immunobiology. Oncotarget. 2016;7:6506–20.

  43. 43.

    Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med. 2005;11:312–9.

  44. 44.

    Ino K, Yamamoto E, Shibata K, et al. Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: Its association with disease progression and survival. Clin Cancer Res. 2008;14:2310–7.

  45. 45.

    Ino K, Yoshida N, Kajiyama H, et al. Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer. Br J Cancer. 2006;95:1555–61.

  46. 46.

    Liu J, Liu Y, Wang W, Wang C, Che Y. Expression of immune checkpoint molecules in endometrial carcinoma. Exp Ther Med. 2015;10:1947–52.

  47. 47.

    Strickland KC, Howitt BE, Shukla SA, et al. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget. 2016;7:13587–98.

  48. 48.

    Joneja U, Vranic S, Swensen J, et al. Comprehensive profiling of metaplastic breast carcinomas reveals frequent overexpression of programmed death-ligand 1. J Clin Pathol. 2016;70:255–9.

  49. 49.

    Thompson E, Taube JM, Elwood H, et al. The immune microenvironment of breast ductal carcinoma in situ. Mod Pathol. 2016;29:249–58.

  50. 50.

    Mansfield AS, Heikkila PS, Vaara AT, von Smitten KA, Vakkila JM, Leidenius MH. Simultaneous Foxp3 and IDO expression is associated with sentinel lymph node metastases in breast cancer. BMC Cancer. 2009;9:231.

  51. 51.

    Soliman HH, Minton SE, Han HS, et al. A phase I study of indoximod in patients with advanced malignancies. Oncotarget. 2016;7:22928–38.

  52. 52.

    Soliman HH, Jackson E, Neuger T, et al. A first in man phase I trial of the oral immunomodulator, indoximod, combined with docetaxel in patients with metastatic solid tumors. Oncotarget. 2014;5:8136–46.

  53. 53.

    Beatty GL, O’Dwyer PJ, Clark J, et al. First-in-human phase I study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin Cancer Res. 2017;23:3269–76.

  54. 54.

    Soliman H, Minton SE, Ismail-Khan R, et al. A phase 2 study of ad.p53 DC vaccine in combination with indoximod in metastatic solid tumors. J Clin Oncol. 2017;32(15_suppl).

  55. 55.

    Spira A, Hamid O, Bauer T, Borges VF, Wasser JS, Smith DC. Efficacy/safety of epacadostat plus pembrolizumab in triple-negative breast cancer and ovarian cancer: Phase I/II ECHO-202 study. J Clin Oncol. 2017;35(15_suppl):1103.

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The authors would like to acknowledge the skill and expertise of the University of Virginia Biorepository and Tissue Research Facility in the construction of Tumor Microarrays.

Author information


  1. University of Virginia Department of Pathology, Charlottesville, Virginia, USA

    • Erik A. Dill
    • , Timothy N. Bullock
    •  & Anne M. Mills
  2. University of Virginia Department of Medicine, Division of Hematology & Oncology, Charlottesville, Virginia, USA

    • Patrick M. Dillon


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Conflict of interest

towards increased tumoral expressioPMD participates in trials sponsored by BMS, Pfizer, Lilly, Merck, Newlink, Abb-vie, Novartis, Seattle Genetics and Genentech.The remaining authors declare that they have no conflict of interest.

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Correspondence to Anne M. Mills.

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