Expression of Tryptophan 2,3-Dioxygenase in Metastatic Uveal Melanoma
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 microenvironmen...
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doaj-15a969d36e354c64bb672361440f3e502020-11-25T01:45:09ZengMDPI AGCancers2072-66942020-02-0112240510.3390/cancers12020405cancers12020405Expression of Tryptophan 2,3-Dioxygenase in Metastatic Uveal MelanomaMizue Terai0Eric Londin1Ankit Rochani2Emma Link3Bao Lam4Gagan Kaushal5Alok Bhushan6Marlana Orloff7Takami Sato8Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USAComputational Medicine Center, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USAUveal 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.https://www.mdpi.com/2072-6694/12/2/405uveal melanomametastatic uveal melanomaliver metastatictryptophan 2,3- dioxygenasetdotryptophankynureninelcmstumor microenvironmentimmunotherapy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mizue Terai Eric Londin Ankit Rochani Emma Link Bao Lam Gagan Kaushal Alok Bhushan Marlana Orloff Takami Sato |
spellingShingle |
Mizue Terai Eric Londin Ankit Rochani Emma Link Bao Lam Gagan Kaushal Alok Bhushan Marlana Orloff Takami Sato Expression of Tryptophan 2,3-Dioxygenase in Metastatic Uveal Melanoma Cancers uveal melanoma metastatic uveal melanoma liver metastatic tryptophan 2,3- dioxygenase tdo tryptophan kynurenine lcms tumor microenvironment immunotherapy |
author_facet |
Mizue Terai Eric Londin Ankit Rochani Emma Link Bao Lam Gagan Kaushal Alok Bhushan Marlana Orloff Takami Sato |
author_sort |
Mizue Terai |
title |
Expression of Tryptophan 2,3-Dioxygenase in Metastatic Uveal Melanoma |
title_short |
Expression of Tryptophan 2,3-Dioxygenase in Metastatic Uveal Melanoma |
title_full |
Expression of Tryptophan 2,3-Dioxygenase in Metastatic Uveal Melanoma |
title_fullStr |
Expression of Tryptophan 2,3-Dioxygenase in Metastatic Uveal Melanoma |
title_full_unstemmed |
Expression of Tryptophan 2,3-Dioxygenase in Metastatic Uveal Melanoma |
title_sort |
expression of tryptophan 2,3-dioxygenase in metastatic uveal melanoma |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-02-01 |
description |
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. |
topic |
uveal melanoma metastatic uveal melanoma liver metastatic tryptophan 2,3- dioxygenase tdo tryptophan kynurenine lcms tumor microenvironment immunotherapy |
url |
https://www.mdpi.com/2072-6694/12/2/405 |
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