Expression of Tryptophan 2,3-Dioxygenase in Metastatic Uveal Melanoma
Mizue Terai1, Eric Londin2, Ankit Rochani3
1Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Abstract:
Uveal melanoma (UM) is the most common primary eye malignancy in adults and up to 50% of patients subsequently develop systemic metastasis. Metastatic uveal melanoma (MUM) is highly resistant to immunotherapy. One of the mechanisms for resistance would be the immune-suppressive tumor microenvironment. Here, we have investigated the role of tryptophan 2,3-dioxygenase (TDO) in UM. Both TDO and indoleamine 2,3-dioxygenase (IDO) catalyze tryptophan and produce kynurenine, which could cause inhibition of T cell immune responses. We first studied the expression of TDO on tumor tissue specimens obtained from UM hepatic metastasis. High expression of TDO protein was confirmed in all hepatic metastasis. TDO was positive in both normal hepatocytes and the tumor cells with relatively higher expression in tumor cells. On the other hand, IDO protein remained undetectable in all of the MUM specimens. UM cell lines established from metastasis also expressed TDO protein and increasing kynurenine levels were detected in the supernatant of MUM cell culture. In TCGA database, higher TDO2 expression in primary UM significantly correlated to BAP1 mutation and monosomy 3. These results indicate that TDO might be one of the key mechanisms for resistance to immunotherapy in UM.
Insights
Metastatic uveal melanoma (MUM) shows resistance to immunotherapy due to an immune-suppressive tumor microenvironment. Researchers found tryptophan 2,3-dioxygenase (TDO) is highly expressed in MUM, suggesting it
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Uveal melanoma (UM) is the most common primary eye cancer in adults.
- Metastatic UM (MUM) is highly resistant to immunotherapy, potentially due to an immune-suppressive tumor microenvironment.
- Tryptophan-catabolizing enzymes like TDO and IDO produce kynurenine, which inhibits T cell responses.
Purpose of the Study:
- To investigate the role of tryptophan 2,3-dioxygenase (TDO) in uveal melanoma.
- To determine if TDO contributes to immunotherapy resistance in metastatic UM.
Main Methods:
- Analysis of TDO protein expression in human UM hepatic metastasis tissue specimens.
- Detection of indoleamine 2,3-dioxygenase (IDO) protein in MUM specimens.
- Assessment of TDO protein expression and kynurenine production in UM cell lines.
- Correlation analysis of TDO2 expression with BAP1 mutation and monosomy 3 in the TCGA database.
Main Results:
- High TDO protein expression was confirmed in all UM hepatic metastasis samples, with higher levels in tumor cells compared to normal hepatocytes.
- IDO protein was undetectable in all MUM specimens.
- UM cell lines expressed TDO and released kynurenine into the cell culture supernatant.
- Higher TDO2 expression in primary UM correlated significantly with BAP1 mutation and monosomy 3.
Conclusions:
- TDO is highly expressed in metastatic uveal melanoma.
- TDO and subsequent kynurenine production may be a key mechanism driving immunotherapy resistance in UM.
- TDO represents a potential therapeutic target for overcoming immunotherapy resistance in UM.
