Inhibition of Tryptophan-Dioxygenase Activity Increases the Antitumor Efficacy of Immune Checkpoint Inhibitors

Abstract

◥Tryptophan 2,3-dioxygenase (TDO) is an enzyme that degrades tryptophan into kynurenine and thereby induces immunosuppression. Like indoleamine 2,3-dioxygenase (IDO1), TDO is considered as a relevant drug target to improve the efficacy of cancer immunotherapy. However, its role in various immunotherapy settings has not been fully characterized. Here, we described a new small-molecule inhibitor of TDO that can modulate kynurenine and tryptophan in plasma, liver, and tumor tissue upon oral administration. We showed that this compound improved the ability of anti-CTLA4 to induce rejection of CT26 tumors expressing TDO. To better characterize TDO as a therapeutic target, we used TDO-KO mice and found that anti-CTLA4 or anti-PD1 induced rejection of MC38 tumors in TDO-KO, but not in wild-type mice. As MC38 tumors did not express TDO, we related this result to the high systemic tryptophan levels in TDO-KO mice, which lack the hepatic TDO needed to contain blood tryptophan. The antitumor effectiveness of anti-PD1 was abolished in TDO-KO mice fed on a tryptophan-low diet that normalized their blood tryptophan level. MC38 tumors expressed IDO1, which could have limited the efficacy of anti-PD1 in wild-type mice and could have been overcome in TDO-KO mice due to the high levels of tryptophan. Accordingly, treatment of mice with an IDO1 inhibitor improved the efficacy of anti-PD1 in wild-type, but not in TDO-KO, mice. These results support the clinical development of TDO inhibitors to increase the efficacy of immunotherapy of TDO-expressing tumors and suggest their effectiveness even in the absence of tumoral TDO expression.See article by Hoffmann et al., p. 19

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

“…TDO was shown to be a promising therapeutic target to improve immune response to cancer cells (178). A recent study by Schramme et al demonstrated that TDO inhibition increases the antitumor efficacy of immune checkpoint inhibitors (179).…”

Tryptophan 2,3-Dioxygenase Expression Identified in Murine Decidual Stromal Cells Is Not Essential for Feto-Maternal Tolerance

“…As an indication of the enzymatic activity of IDO1 and TDO, we measured kynurenine in the serum of pregnant mice (Figure 3). We showed in a previous report that circulating kynurenine in non-pregnant mice was produced by IDO1 and not by hepatic TDO, as it was completely absent in IDO1-KO mice, while it was slightly increased in TDO-KO mice in which tryptophan levels were elevated (30). We confirmed this result at early pregnancy time points, when serum kynurenine in TDO-KO mice was identical or slightly higher than in WT mice, while it was not detectable in double IDO1-TDO-KO mice.…”

“…In pathology, TDO is expressed by tumor cells of all hepatocarcinomas and 25% of glioblastomas, as well as by pericytes of vascular structures in focal spots of most late stage tumors, and by pericytes in pulmonary inflammatory lesions (27,28). TDO inhibition of either tumoral or hepatic TDO favors immune-mediated tumor rejection and increases the efficacy of immune checkpoint inhibitors (29,30). TDO was also identified in pericytes and interstitial syncytiotrophoblasts in the human placenta (27).…”

Tryptophan Catabolism and Response to Therapy in Locally Advanced Rectal Cancer (LARC) Patients

“…Tryptophan is the precursor of several active compounds, collectively named TRYCATs ( Figure 1 ). At the tumor microenvironment, TRP catabolism is promoted by indoleamine 2,3-dioxygenase (IDO1) overexpression under pro-inflammatory conditions, and it plays an important role in modulating antitumor immune response ( 18 – 20 ). In CRC, IDO1 expression at the tumor invasion front correlates with disease progression and worse clinical outcome ( 21 ) and is associated with the frequency of liver metastases ( 22 ).…”