Inhibition of tryptophan-dioxygenase activity increases the antitumor efficacy of immune checkpoint inhibitors

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. We related this result to the high systemic tryptophan levels in TDO-KO mice, which lack hepatic TDO needed to contain blood tryptophan, as MC38 tumors did not express TDO. The antitumor effectiveness of anti-PD1 was abolished in TDO-KO mice fed with 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