Targeting Tryptophan Catabolism in Cancer Immunotherapy Era: Challenges and Perspectives

Abstract

Metabolism of tryptophan (Trp), an essential amino acid, represent a major metabolic pathway that both promotes tumor cell intrinsic malignant properties as well as restricts antitumour immunity, thus emerging as a drug development target for cancer immunotherapy. Three cytosolic enzymes, namely indoleamine 2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan 2,3-dioxygenase (TDO2), catalyzes the first-rate limiting step of the degradation of Trp to kynurenine (Kyn) and modulates immunity toward immunosuppression mainly through the aryl hydrocarbon receptor (AhR) activation in numerous types of cancer. By restoring antitumor immune responses and synergizing with other immunotherapies, the encouraging preclinical data of IDO1 inhibitors has dramatically failed to translate into clinical success when combined with immune checkpoints inhibitors, reigniting the debate of combinatorial approach. In this review, we i) provide comprehensive evidences on immunomodulatory role of the Trp catabolism metabolites that highlight this pathway as relevant target in immuno-oncology, ii)ii) discuss underwhelming results from clinical trials investigating efficacy of IDO1 inhibitors and underlying mechanisms that might have contributed to this failure, and finally, iii) discuss the current state-of-art surrounding alternative approaches of innovative antitumor immunotherapies that target molecules of Trp catabolism as well as challenges and perspectives in the era of immunotherapy.

Keywords: cancer; immunotherapy; indoleamine 2,3-dioxygenase; kynurenine; tryptophan metabolism.

Figure 1

The tryptophan catabolic pathway in cancer. (A) Provided by dietary intake, the essential amino acid Trp is catabolized into Kyn through three rate-limiting enzymes: TDO in the liver and IDO1/IDO2 in peripheral tissues. In tumor, IDO1 transforms Trp to Kyn by cleaving the 2,3-double bond of the indole ring, producing N-formyl kynurenine (NFK) that becomes rapidly and spontaneously converted into Kyn. The latter catabolite is further converted into downstream active intermediates, including hydroxykynurenine, anthranilic acid, 3-HAA, quinolinic acid and picolinic acid. The end-products of the pathway are NAD⁺ and others molecules that fuel cellular metabolism. (B) Depletion of Trp in T cells suppresses activity in the mTORC1 signaling pathway and activates GCN2, inducing T cell dysfunction and leading to tumor-associated immunosuppression. Increase Kyn level in the TME leads to AhR in multiple tumor-associated immune cells, promoting immunosuppression functions. 3-HAA, 3-hydroxyanthranililic acid; AhR, aryl hydrocarbon receptor; GCN2, general control over nonderepressible 2; IDO1, indoleamine 2,3-dioxygenase (IDO1); Kyn, kynurenine; NAD⁺, nicotinamide adenine dinucleotide; mTORC1, mammalian target of rapamycin complex 1; NFK, N-formyl kynurenine; TDO, tryptophan 2,3-dioxygenase; TME, tumor microenvironment; Trp, tryptophan.

Figure 2

Immunological effects of kynurenine and tryptophan metabolites in cancer. Effects of Trp depletion and Kyn augmentation on CD8 T cells, regulatory T cells, myeloid cells (MDSC, M2, DC) and tumor cells. DC, dendritic cell; Kyn, kynurenine; IL-6, interleukin 6; MDSC, myeloid-derived suppressor cell; M2, type 2 macrophage; Trp, tryptophan.