A Role for Tryptophan-2,3-dioxygenase in CD8 T-cell Suppression and Evidence of Tryptophan Catabolism in Breast Cancer Patient Plasma

Tryptophan catabolism is an attractive target for reducing tumor progression and improving antitumor immunity in multiple cancers. Tumor infiltration by CD8 T cells correlates with improved prognosis in triple-negative breast cancer (TNBC) and a significant effort is underway to improve CD8 T-cell antitumor activity. In this study, primary human immune cells were isolated from the peripheral blood of patients and used to demonstrate that the tryptophan catabolite kynurenine induces CD8 T-cell death. Furthermore, it is demonstrated that anchorage-independent TNBC utilizes the tryptophan-catabolizing enzyme tryptophan 2,3-dioxygenase (TDO) to inhibit CD8 T-cell viability. Publicly available data revealed that high TDO2, the gene encoding TDO, correlates with poor breast cancer clinical outcomes, including overall survival and distant metastasis-free survival, while expression of the gene encoding the more commonly studied tryptophan-catabolizing enzyme, IDO1 did not. Metabolomic analysis, using quantitative mass spectrometry, of tryptophan and its catabolites, including kynurenine, in the plasma from presurgical breast cancer patients (n = 77) and 40 cancer-free donors (n = 40) indicated a strong correlation between substrate and catabolite in both groups. Interestingly, both tryptophan and kynurenine were lower in the plasma from patients with breast cancer compared with controls, particularly in women with estrogen receptor (ER)-negative and stage III and IV breast cancer. Implications: This study underscores the importance of tryptophan catabolism, particularly in aggressive disease, and suggests that future pharmacologic efforts should focus on developing drugs that target both TDO and IDO1.