• Kashif Asghar Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), Lahore, Pakistan
  • Asif Loya Pathology department, SKMCH&RC


Therapeutic manipulation of immune system in cancer has been an extensive area of research in the field of oncoimmunology. Immunotherapy helps the immune system to combat against cancer. Tumour cells take an edge of immunosuppressive mechanisms and inhibit antitumour immune responses. Indoleamine 2,3 dioxygenase (IDO) is an immunosuppressive enzyme which is involved in tumour immune escape mechanism in various cancers. IDO can degrade the tryptophan into kynurenines and has an ability to enhance the immune tolerance through mammalian target of rapamycin pathway general control nonderepressible 2 (GCN2) pathway and induction of regulatory T (T-regs) cells. IDO-induced T-regs suppress the local immune responses in the tumour microenvironment and promote metastasis. IDO overexpression in various cancers is associated with poor prognosis. Several preclinical and clinical trials have been proceeding and recommend that IDO inhibitor may be an influential tool against a wide range of cancers. IDO inhibitors as adjuvant therapeutic agents may also have clinical implications. Thus, IDO has the potential to be used as an immunotherapeutic target. This review discusses the promising role of IDO in cancer and its implication in immunotherapy.

Key words: Breast cancer, colorectal cancer, haematological malignancies, immunotherapy, indoleamine 2,3-dioxygenase, pancreatic cancer, prostate cancer

Author Biography

Kashif Asghar, Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), Lahore, Pakistan
Dr. Kashif Asghar (PhD)
Junior Research Scientist, Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital & Research Centre
7A, Block R3, Johar Town, Lahore, Punjab  54000, Pakistan
Phone: +92-42-35905000 Ext: 4365
Fax: +92-42-35945206


Oiseth SJ, Aziz MS. Cancer immunotherapy: A brief review of the history, possibilities, and challenges ahead. J Cancer Metastasis Treat 2017;3:250-61.

Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: The beginning of the end of cancer? BMC Med 2016;14:73.

Challis GB, Stam HJ. The spontaneous regression of cancer. A review of cases from 1900 to 1987. Acta Oncol 1990;29:545-50.

Mansfield AS, Heikkila PS, Vaara AT, et al. Simultaneous foxp3 and IDO expression is associated with sentinel lymph node metastases in breast cancer. BMC Cancer 2009;9:231.

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.

Katz JB, Muller AJ, Prendergast GC. Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev 2008;222:206-21.

Munn DH, Sharma MD, Baban B, et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 2005;22:633-42.

Ogata S, Takeuchi M, Fujita H, et al. Apoptosis induced by nicotinamide-related compounds and quinolinic acid in HL-60 cells. Biosci Biotechnol Biochem 2000;64:327-32.

Nakamura T, Shima T, Saeki A, et al. Expression of indoleamine 2,3-dioxygenase and the recruitment of foxp3-expressing regulatory T cells in the development and progression of uterine cervical cancer. Cancer Sci 2007;98:874-81.

Grohmann U, Fallarino F, Puccetti P. Tolerance, DCs and tryptophan: Much ado about IDO. Trends Immunol 2003;24:242-8.

Moffett JR, Espey MG, Namboodiri MA. Antibodies to quinolinic acid and the determination of its cellular distribution within the rat immune system. Cell Tissue Res 1994;278:461-9.

Yoshida R, Park SW, Yasui H, Takikawa O. Tryptophan degradation in transplanted tumor cells undergoing rejection. J Immunol 1988;141:2819-23.

Malina HZ, Martin XD. Indoleamine 2,3-dioxygenase: Antioxidant enzyme in the human eye. Graefes Arch Clin Exp Ophthalmol 1996;234:457-62.

Hwu P, Du MX, Lapointe R, Do M, Taylor MW, Young HA, et al. Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J Immunol 2000;164:3596-9.

Munn DH, Sharma MD, Lee JR, et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 2002;297:1867-70.

Godin-Ethier J, Hanafi LA, Piccirillo CA, Lapointe R. Indoleamine 2,3-dioxygenase expression in human cancers: Clinical and immunologic perspectives. Clin Cancer Res 2011;17:6985-91.

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252-64.

Sadun RE, Sachsman SM, Chen X, et al. Immune signatures of murine and human cancers reveal unique mechanisms of tumor escape and new targets for cancer immunotherapy. Clin Cancer Res 2007;13:4016-25.

Jacquemier J, Bertucci F, Finetti P, et al. High expression of indoleamine 2,3-dioxygenase in the tumour is associated with medullary features and favourable outcome in basal like breast carcinoma. Int J Cancer 2012;130:96-104.

Levina V, Su Y, Gorelik E. Immunological and nonimmunological effects of indoleamine 2,3-dioxygenase on breast tumor growth and spontaneous metastasis formation. Clin Dev Immunol 2012;2012:173029.

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.

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;132:967-77.

Yu J, Du W, Yan F, et al. Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis inpatients with breast cancer. J Immunol 2013;190:3783-97.

Isla Larrain MT, Rabassa ME, Lacunza E, Barbera A, Cretón A, Segal-Eiras A, 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.

Salvadori ML, da Cunha Bianchi PK, Gebrim LH, et al. Effect of the association of 1-methyl-DL-tryptophan with paclitaxel on the expression of indoleamine 2,3-dioxygenase in cultured cancer cells from patients with breast cancer. Med Oncol 2015;32:248.

Chen Y, Xia R, Huang Y, et al. An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy. Nat Commun 2016;7:13443.

Kim S, Park S, Cho MS, et al. Strong correlation of indoleamine 2,3-dioxygenase 1 expression with basal-like phenotype and increased lymphocytic infiltration in triplenegative breast cancer. J Cancer 2017;8:124-30.

Noonepalle SK, Gu F, Lee EJ, et al. Promoter methylation modulates indoleamine 2,3-dioxygenase 1 induction by activated T cells in human breast cancers. Cancer Immunol Res 2017;5:330-44.

Engin A, Gonul II, Engin AB, et al. Relationship between indoleamine 2,3-dioxygenase activity and lymphatic invasion propensity of colorectal carcinoma. World J Gastroenterol 2016;22:3592-601.

Ferdinande L, Decaestecker C, Verset L, et al. Clinicopathological significance of indoleamine 2,3-dioxygenase 1 expression in colorectal cancer. Br J Cancer 2012;106:141-7.

Thaker AI, Rao MS, Bishnupuri KS, et al. IDO1 metabolites activate β-catenin signaling to promote cancer cell proliferation and colon tumorigenesis in mice. Gastroenterology 2013;145:416-250.

Eyraud D, Granger B, Zahr N, et al. Measurement of indoleamine 2, 3 dioxygenase activity in colorectal cancer: A Controlled group study. J Clin Cell Immunol 2015;6:374.

Chen IC, Lee KH, Hsu YH, et al. Expression pattern and clinicopathological relevance of the indoleamine 2,3-dioxygenase 1/Tryptophan 2,3-dioxygenase protein in colorectal cancer. Dis Markers 2016;2016:8169724.

Hoshi M, Ito H, Fujigaki H, et al. Indoleamine 2,3-dioxygenase is highly expressed in human adult T-cell leukemia/lymphoma and chemotherapy changes tryptophan catabolism in serum and reduced activity. Leuk Res 2009;33:39-45.

Lindström V, Aittoniemi J, Jylhävä J, et al. Indoleamine 2,3-dioxygenase activity and expression in patients with chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk 2012;12:363-5.

Folgiero V, Natale D, Pagliara D, et al. Indoleamine 2, 3-dioxygenase-1 (IDO1) Is expressed by a subset of childhood acute myeloid leukemias and restrains IFN-γ production by T cells. Blood 2012;120:21.

Nakamura N, Hara T, Shibata Y, et al. Combination of indoleamine 2,3-dioxygenaseinhibitorand cytotoxic agents is a novel therapeutic option for non-hodgkin lymphoma. Blood 2013;122:21.

Liu XQ, Lu K, Feng LL, et al. Up-regulated expression of indoleamine 2,3-dioxygenase 1 in non-hodgkin lymphoma correlates with increased regulatory T-cell infiltration. Leuk Lymphoma 2014;55:405-14.

Choe JY, Yun JY, Jeon YK, et al. Indoleamine 2,3-dioxygenase (IDO) is frequently expressed in stromal cells of hodgkin lymphoma and is associated with adverse clinical features: A retrospective cohort study. BMC Cancer 2014;14:335.

Folgiero V, Goffredo BM, Filippini P, et al. Indoleamine 2,3-dioxygenase 1 (IDO1) activity in leukemia blasts correlates with poor outcome in childhood acute myeloid leukemia. Oncotarget 2014;5:2052-64.

Mansour I, Zayed RA, Said F, et al. Indoleamine 2,3-dioxygenase and regulatory T cells in acute myeloid leukemia. Hematology 2016;21:447-53.

Wong MC, Goggins WB, Wang HH, et al. Global incidence and mortality for prostate cancer: Analysis of temporal patterns and trends in 36 countries. Eur Urol 2016;70:862‑74.

Feder-Mengus C, Wyler S, Hudolin T, et al. High expression of indoleamine 2,3-dioxygenase gene in prostate cancer. Eur J Cancer 2008;44:2266-75.

Provenzano M, Feder-Mengus C, Wyler S, et al. Indoleamine 2,3- dioxygenase (IDO) expression and malignant transformation in prostate cancer. J Clin Oncol 2008;26:15.

Gray A, de la Luz Garcia-Hernandez M, van West M, et al. Prostate cancer immunotherapy yields superior long-term survival in TRAMP mice when administered at an early stage of carcinogenesis prior to the establishment of tumorassociated immunosuppression at later stages. Vaccine 2009;27 Suppl 6:G52-9.

Matos YS, Brito RB, Matheus LS, et al. The role of indoleamine 2,3-dioxygenase (IDO) on pc-3 prostate cancer cells viability. FASEB J 2016;30:698-718.

Witkiewicz A, Williams TK, 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;206:849-54.

Watanabe MA, Oda JM, Amarante MK, et al. Regulatory T cells and breast cancer: Implications for immunopathogenesis. Cancer Metastasis Rev 2010;29:569‑79.

Ikemoto T, Yamaguchi T, Morine Y, et al. Clinical roles of increased populations of foxp3+CD4+ T cells in peripheral blood from advanced pancreatic cancer patients. Pancreas 2006;33:386-90.

Kobayashi N, Kubota K, Kato S, et al. FOXP3+ regulatory T cells and tumoral indoleamine 2,3-dioxygenase expression predicts the carcinogenesis of intraductal papillary mucinous neoplasms of the pancreas. Pancreatology 2010;10:631-40.

Ikemoto T, Shimada M, Komatsu M, et al. Indoleamine 2,3-dioxygenase affects the aggressiveness of intraductal papillary mucinous neoplasms through foxp3+CD4+CD25+ T cells in peripheral blood. Pancreas 2013;42:130-4.

Duan X, Deng L, Chen X, et al. Clinical significance of the immunostimulatory MHC class I chain-related molecule A and NKG2D receptor on NK cells in pancreatic cancer. Med Oncol 2011;28:466-74.

Peng YP, Zhang JJ, Liang WB, et al. Elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates natural killer cell dysfunction. BMC Cancer 2014;14:738.

Metz R, Rust S, Duhadaway JB, et al. IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan. Oncoimmunology 2012;1:1460-8.

Liu X, Shin N, Koblish HK, et al. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood 2010;115:3520-30.

Koblish HK, Hansbury MJ, Bowman KJ, 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;9:489-98.

Mautino MR, Jaipuri FA, Waldo J, et al. NLG919, a novel

indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy. Am Assoc Cancer Res 2013;73:8.

Moon YW, Hajjar J, Hwu P, et al. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J Immunother Cancer 2015;3:51.

Vonderheide RH, Burg JM, Mick R, et al. Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors. Oncoimmunology 2013;2:e23033.

Hoffmann J, Vitale I, Buchmann B, et al. Improved cellular pharmacokinetics and pharmacodynamics underlie the wide anticancer activity of sagopilone. Cancer Res 2008;68:5301‑8.

Galluzzi L, Senovilla L, Vacchelli E, et al. Trial watch: Dendritic cell-based interventions for cancer therapy. Oncoimmunology 2012;1:1111-34.

Vacchelli E, Vitale I, Eggermont A, et al. Trial watch: Dendritic cell-based interventions for cancer therapy. Oncoimmunology 2013;2:e25771.

Ball HJ, Yuasa HJ, Austin CJ, et al. Indoleamine 2,3-dioxygenase-2; a new enzyme in the kynurenine pathway. Int J Biochem Cell Biol 2009;41:467-71.

How to Cite
Asghar K, Loya A. INDOLEAMINE 2,3 DIOXYGENASE AS AN IMMUNOTHERAPEUTIC TARGET BRINGS A NEW HOPE FOR CANCER PATIENTS. J Cancer Allied Spec [Internet]. 2018Sep.30 [cited 2022May26];4(3). Available from: