Targeting the indoleamine 2,3-dioxygenase pathway in cancer

Abstract

Tumor cells escape the immune surveillance system of the host through a process called immune tolerance. Immunotherapy targets molecules that serve as checks and balances in the regulation of immune response. Indoleamine-2,3-dioxygenase (IDO) is an intracellular enzyme, which through the process of tryptophan depletion exerts an immunosuppressive effect, facilitating immune escape of tumors. This review summarizes our current knowledge on IDO expression in malignancies, the IDO inhibitors that are currently available and those under clinical development.

Keywords: IDO inhibitors; Immune surveillance; Immunomodulatory; Indoleamine 2,3-dioxygenase; Malignancy.

Fig. 1

Mechanisms of IDO pathway activity in immune tolerance. The enzyme IDO catalyzes the initial and rate-limiting step in the catabolism of tryptophan along the kynurenine pathway. Accordingly, IDO can provoke tryptophan shortage, which results in mTORC1 inhibition and GCN2 activation, in turn leading to anergy of effector T cells. Tryptophan’s degradation leads to production of bioactive kynurenine pathway compounds, which activate the AHR, resulting in promotion of Treg differentiation. TC, tumor cell; DC, dendritic cell; MФ, macrophage; EC, endothelial cell; FB, fibroblast; IDO, indoleamine-2,3-dioxygenase 1; Trp, tryptophan; Krn, kynurenine; mTORC1, mechanistic target of rapamycin (serine/threonine kinase) complex 1; GCN2, general control nondepressible-2; AHR, aryl hydrocarbon receptor; Treg, regulatory T cell

Fig. 2

Potential mechanism of combinatory synergism between three methods of immune checkpoint blockade. PD-1 or CTLA4 signaling inhibits proliferation of effector T cells. In addition, some studies have suggested that Tregs are also partly activated by PD-1 or CTLA4 signaling [100]. IDO signaling induces tumor immune tolerance by both suppressing effector T cells and activating Tregs. Therefore, if PD-1 or CTLA-4 signaling blockade is combined with an IDO inhibitor, effector T cells may be further activated and Tregs may be further suppressed. The result could be more effective reversal of immune tolerance and enhanced anti-tumor immune response. APC, antigen-presenting cell; PD-1, programmed cell death-1; PD-L1, programmed cell death-ligand 1; CTLA4, cytotoxic T-lymphocyte-associated protein 4; B7-1/2, peripheral membrane proteins found on activated APCs