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Tryptophan 2,3-dioxygenase in tumor cells is associated with resistance to immunotherapy in renal cell carcinoma.
- Source :
-
Cancer science [Cancer Sci] 2021 Mar; Vol. 112 (3), pp. 1038-1047. Date of Electronic Publication: 2021 Jan 25. - Publication Year :
- 2021
-
Abstract
- Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme associated with immunomodulation through its regulation of the tryptophan-kynurenine (Kyn) pathway in advanced cancers, including metastatic renal cell carcinoma (mRCC). However, the failure of IDO1 inhibitors when used in combination with immune checkpoint inhibitors (ICIs), as observed in clinical trials, raises a number of questions. This study aimed to investigate the association of tryptophan 2,3-dioxygenase (TDO) and IDO1 with cancer development and resistance to immunotherapy in patients with RCC. In our analysis of RCC tissue samples, tissue Kyn levels were elevated in advanced-stage RCC and correlated well with TDO expression levels in RCC tumor cells. In patients with mRCC, TDO rather than IDO1 was expressed in RCC tumor cells, showing a strong association with Kyn expression. Furthermore, immunohistochemical staining of TDO was strongly associated with the staining intensity of forkhead box P3, as well as ICI therapy response and survival in patients with mRCC. Our study is the first to show that TDO expression in tumor tissues is associated with progression and survival, confirming its potential as a predictive biomarker of primary resistance to immunotherapy in patients with mRCC. Our findings suggest that strategies aimed at inhibiting TDO, rather than IDO1, in combination with ICI therapy may aid in the control of mRCC progression.<br /> (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Subjects :
- Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Carcinoma, Renal Cell mortality
Carcinoma, Renal Cell pathology
Cell Line, Tumor
Chemotherapy, Adjuvant
Disease Progression
Drug Resistance, Neoplasm
Female
Humans
Immune Checkpoint Inhibitors pharmacology
Immune Checkpoint Inhibitors therapeutic use
Immunohistochemistry
Indoleamine-Pyrrole 2,3,-Dioxygenase antagonists & inhibitors
Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism
Kidney surgery
Kidney Neoplasms mortality
Kidney Neoplasms pathology
Kynurenine analysis
Kynurenine metabolism
Male
Middle Aged
Nephrectomy
Progression-Free Survival
Tryptophan metabolism
Tryptophan Oxygenase analysis
Tryptophan Oxygenase antagonists & inhibitors
Antineoplastic Combined Chemotherapy Protocols pharmacology
Carcinoma, Renal Cell therapy
Kidney pathology
Kidney Neoplasms therapy
Tryptophan Oxygenase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1349-7006
- Volume :
- 112
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer science
- Publication Type :
- Academic Journal
- Accession number :
- 33410234
- Full Text :
- https://doi.org/10.1111/cas.14797