Abstract
BackgroundIndoleamine 2,3-dioxygenase catalyzes the conversion of tryptophan to kynurenine, an immunosuppressive metabolite involved in T regulatory cell differentiation. Indoleamine 2,3-dioxygenase is expressed in many cancer types, including breast cancer. Here, we analyze kynurenine and tryptophan and their ratio in breast cancer patients and healthy controls.MethodsBreast cancer patients and healthy controls were prospectively enrolled in our study. All subjects underwent blood sample withdrawal at diagnosis or on the day of screening mammography for the healthy controls. Plasmatic kynurenine and tryptophan were determined on a TQ5500 tandem mass spectrometer after chromatographic separation.ResultsWe enrolled 146 healthy controls and 202 women with stages I–III breast cancer of all subtypes. All patients underwent surgery, 126 underwent neoadjuvant chemotherapy with 43 showing a pathological complete response, and 43 underwent adjuvant chemotherapy. We observed significantly higher plasmatic kynurenine, tryptophan and their ratio for the healthy controls compared to patients with breast cancer. We observed a lower plasmatic tryptophan and a higher kynurenine/tryptophan ratio in hormone receptor-negative patients compared to hormone receptor-positive cancers. Lobular cancers showed a lower ratio than any other histologies. Advanced cancers were associated with a lower tryptophan level and higher grades with an increased kynurenine/tryptophan ratio. Pathological complete response was associated with higher kynurenine values. The plasmatic kynurenine, tryptophan and kynurenine/tryptophan ratios were not predictive of survival.ConclusionsThe plasmatic kynurenine, tryptophan and kynurenine/tryptophan ratio could differentiate breast cancer patients from healthy controls. The Kyn/Trp ratio and Trp also showed different values according to hormone receptor status, TNM stage, T grade and histology. These results suggest a rapid metabolism in breast cancer, but no associations with outcome or sensitivity to chemotherapy were observed.
Highlights
Indoleamine 2,3-dioxygenase catalyzes the conversion of tryptophan to kynurenine, an immunosuppressive metabolite involved in T regulatory cell differentiation
All the breast cancer subtypes were included in the study: Luminal A in 29.7%; Luminal B in 44.1%; HER2-enriched in 6.9% and triple-negative breast cancer (TNBC) in 19.3% of the cases
In our study, we showed that plasmatic levels of Kyn, Trp and the Kyn/Trp ratio could differentiate BC patients from healthy CTRLs, but they were not useful for predicting the outcome or sensitivity to chemotherapy
Summary
Indoleamine 2,3-dioxygenase catalyzes the conversion of tryptophan to kynurenine, an immunosuppressive metabolite involved in T regulatory cell differentiation. Indoleamine 2,3-dioxygenase is expressed in many cancer types, including breast cancer. We analyze kynurenine and tryptophan and their ratio in breast cancer patients and healthy controls. Tryptophan (Trp) catabolism is a known mechanism involved in immune system modulation and is widely studied in cancer. Trp is metabolized by indoleamine 2,3-dioxygenase (IDO), by its splice variant IDO2 and by tryptophan 2,3-dioxygenase (TDO) [1]. IDO expression is induced in response to some inflammatory cytokines, such as interferon-γ (IFN-γ), acting as an endogenous mechanism able to control an excessive immune response [5]. IDO is expressed by several tumor types and is correlated with lower cytotoxic cells and higher T regulatory (Treg) cell infiltration at the tumor site, poorer outcome and resistance to treatment [6,7,8,9,10,11,12,13,14,15,16]
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