Explore IDO1

The role of the indoleamine 2,3-dioxygenase 1 (IDO1) pathway is to regulate inflammation and mediate suppression of T cells. This pathway is active in a variety of settings, including maternal-fetal tolerance, autoimmunity, and chronic infection.1,2

IDO1 is a cytosolic enzyme that catalyzes the rate-limiting step in the conversion of tryptophan to kynurenine within the IDO1 pathway. IDO2, a related but less well understood enzyme, has displayed lower tryptophan catabolic activity and a more restricted pattern of expression in humans compared to IDO1.1,3-5

Image: IDO1, tryptophan, and kynurenine

IDO1 expression by antigen-presenting cells (APC) and/or tumor cells may promote immune tolerance through1:

  • Local depletion of tryptophan
  • Local production of kynurenine

The IDO1 pathway in cancer

IDO1 protein expression has been observed in a wide variety of human cancers, including lung, renal, pancreatic, ovarian, cervical, colorectal, prostate, endometrial, melanoma, and acute myelogenous leukemia.6,7

IDO1 expression in tumor cells and/or antigen-presenting cells (APC) within the tumor microenvironment may provide tumors with a mechanism of immune escape.1,4,8

IDO1 expression can result in a shift in local tryptophan and kynurenine levels. Based on preclinical observations, this shift may directly suppress cytotoxic lymphocytes (CTL) and natural killer (NK) cells, and activate effector pathways that may further suppress these cells through the following mechanisms1,4,8,9:

  • Generation, recruitment, and activation of immune-suppressing regulatory T cells (Treg)
  • Recruitment and activation of immune-suppressing myeloid-derived suppressor cells (MDSC)
Image: Tolerogenic state and Treg/MDSC activation and recruitment

IDO1 and cancer immunity

Several in vivo studies have associated IDO1 expression with reduced intratumoral T-cell infiltration, disease progression, and poor prognosis, highlighting the potential of IDO1 as a cancer immunity target.3 Tumors employ multiple mechanisms to evade the immune response, suggesting that an approach involving a combination of targets to re-establish proper effector T-cell function may be warranted.4,9,10

For instance, expression of IDO1 and programmed death-ligand 1 (PD-L1) are strongly correlated within certain tumors.11 These pathways serve distinct but complementary functions that mediate effector T-cell suppression, suggesting that the pathways may act in parallel.1,12 Dual-pathway modulation has been suggested as a potential strategy to overcome tumor immune escape and promote tumor-specific cytotoxicity.3

Image: Expression of IDO1 and programmed death-ligand 1 (PD-L1)

References

  1. Munn DH, Mellor AL. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol. 2016;37:193-207. PMID: 26839260
  2. Johnson TS, Munn DH. Host indoleamine 2,3-dioxygenase: contribution to systemic acquired tumor tolerance. Immunol Invest. 2012;41:765-797. PMID: 23017145
  3. Moon YW, Hajjar J, Hwu P, Naing A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J Immunother Cancer. 2015;3:51. doi:10.1186/s40425-015-0094-9. PMID: 26674411
  4. Prendergast GC, 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. PMID: 24711084
  5. Metz R, Smith C, DuHadaway JB, 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. PMID: 24402311
  6. Théate 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. PMID: 25271151
  7. Curti A, Aluigi M, Pandolfi S, et al. Acute myeloid leukemia cells constitutively express the immunoregulatory enzyme indoleamine 2,3-dioxygenase. Leukemia. 2007;21:353-355. PMID: 17170728
  8. Platten M, von Knebel Doeberitz N, Oezen I, Wick W, Ochs K. Cancer immunotherapy by targeting IDO1/TDO and their downstream effectors. Front Immunol. 2015;5:673. doi:10.3389/fimmu.2014.00673. PMID: 25628622
  9. Holmgaard RB, Zamarin D, Li Y, et al. Tumor-expressed IDO recruits and activates MDSCs in a Treg-dependent manner. Cell Rep. 2015;13:412-424. PMID: 26411680
  10. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10. PMID: 23890059
  11. Spranger S, Spaapen RM, Zha Y, et al. Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci Transl Med. 2013;5:200ra116. doi:10.1126/scitranslmed.3006504. PMID: 23986400
  12. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-264. PMID: 22437870

Related links

Information based on tumor type