The Kynurenine Pathway and Cancer: Why Keep It Simple When You Can Make It Complicated

Abstract

The kynurenine pathway has been highlighted as a gatekeeper of immune-privileged sites through its ability to generate from tryptophan a set of immunosuppressive metabolic intermediates. It additionally constitutes an important source of cellular NAD⁺ for the organism. Hijacking of its immunosuppressive functions, as recurrently observed in multiple cancers, facilitates immune evasion and promotes tumor development. Based on these observations, researchers have focused on characterizing indoleamine 2,3-dioxygenase (IDO1), the main enzyme catalyzing the first and limiting step of the pathway, and on developing therapies targeting it. Unfortunately, clinical trials studying IDO1 inhibitors have thus far not met expectations, highlighting the need to unravel this complex signaling pathway further. Recent advances demonstrate that these metabolites additionally promote tumor growth, metastatic dissemination and chemoresistance by a combination of paracrine and autocrine effects. Production of NAD⁺ also contributes to cancer progression by providing cancer cells with enhanced plasticity, invasive properties and chemoresistance. A comprehensive survey of this complexity is challenging but necessary to achieve medical success.

Keywords: NAD; kynurenine; tumor initiation and progression.

Figure 1

Schematic representation of the kynurenine pathway. Enzymes are written in red. IDO: indoleamine 2-3-dioxygenase, TDO2: Tryptophan 2,3-dioxygenase 2, AFMID: arylformamidase, KYNU: Kynureninase, 3HAO: 3-hydroxyanthranilate 3,4-dioxygenase, QPRT: quinolinate phosphoribosyltransferase. Immunosuppression and NAD⁺-producing modules are highlighted.

Figure 2

Pleiotropic kynurenine protumoral functions. Kynurenine production, resulting from IDO and/or TDO induction, leads to the AhR receptor activation to promote cancer cell proliferation, chromosomal instability, neoangiogenesis, immune evasion, metastatic dissemination and chemoresistance. AhR-independent functions of kynurenine also promote tumor growth. Tryptophan depletion, resulting from the kynurenine pathway activation, additionally contributes to the establishment of an immune tolerant environment.

Figure 3

Different outcomes of kynurenine pathway alterations in cancer. Panel (A): the aberrant induction of the first module, as observed in colorectal carcinomas (CRC), leads to the accumulation of kynurenine, thereby promoting tumor growth and immune evasion. Panel (B): aberrant induction of the two modules, as observed in triple-negative breast cancers (TNBC), fuels cells with NAD⁺ and promotes cancer cell dissemination. Panel (C): Inactivation of the second module, as observed in clear cell renal cell carcinoma (ccRCC), leads to the accumulation of quinolinic acid and favors tumor development. (D): Inactivation of both modules, as observed in hepatomacarcinomas, prevents NAD⁺ production, favors genomic instability and, thereby, tumor development.