Tryptophan 2,3-dioxygenase in tumor cells is associated with resistance to immunotherapy in renal cell carcinoma.
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Carcinoma, Renal Cell
/ mortality
Cell Line, Tumor
Chemotherapy, Adjuvant
Disease Progression
Drug Resistance, Neoplasm
Female
Humans
Immune Checkpoint Inhibitors
/ pharmacology
Immunohistochemistry
Indoleamine-Pyrrole 2,3,-Dioxygenase
/ antagonists & inhibitors
Kidney
/ pathology
Kidney Neoplasms
/ mortality
Kynurenine
/ analysis
Male
Middle Aged
Nephrectomy
Progression-Free Survival
Tryptophan
/ metabolism
Tryptophan Oxygenase
/ analysis
IDO1
TDO
biomarker
immune checkpoint inhibitor
renal cell carcinoma
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Mar 2021
Mar 2021
Historique:
received:
12
11
2020
revised:
24
12
2020
accepted:
03
01
2021
pubmed:
8
1
2021
medline:
18
3
2021
entrez:
7
1
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33410234
doi: 10.1111/cas.14797
pmc: PMC7935775
doi:
Substances chimiques
IDO1 protein, human
0
Immune Checkpoint Inhibitors
0
Indoleamine-Pyrrole 2,3,-Dioxygenase
0
Kynurenine
343-65-7
Tryptophan
8DUH1N11BX
Tryptophan Oxygenase
EC 1.13.11.11
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1038-1047Informations de copyright
© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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