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QDPR deficiency drives immune suppression in pancreatic cancer.
- Source :
-
Cell metabolism [Cell Metab] 2024 May 07; Vol. 36 (5), pp. 984-999.e8. Date of Electronic Publication: 2024 Apr 19. - Publication Year :
- 2024
-
Abstract
- The relevance of biopterin metabolism in resistance to immune checkpoint blockade (ICB) therapy remains unknown. We demonstrate that the deficiency of quinoid dihydropteridine reductase (QDPR), a critical enzyme regulating biopterin metabolism, causes metabolite dihydrobiopterin (BH2) accumulation and decreases the ratio of tetrahydrobiopterin (BH4) to BH2 in pancreatic ductal adenocarcinomas (PDACs). The reduced BH4/BH2 ratio leads to an increase in reactive oxygen species (ROS) generation and a decrease in the distribution of H3K27me3 at CXCL1 promoter. Consequently, myeloid-derived suppressor cells are recruited to tumor microenvironment via CXCR2 causing resistance to ICB therapy. We discovered that BH4 supplementation is capable to restore the BH4/BH2 ratio, enhance anti-tumor immunity, and overcome ICB resistance in QDPR-deficient PDACs. Tumors with lower QDPR expression show decreased responsiveness to ICB therapy. These findings offer a novel strategy for selecting patient and combining therapies to improve the effectiveness of ICB therapy in PDAC.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Animals
Mice
Tumor Microenvironment
Cell Line, Tumor
Immune Checkpoint Inhibitors therapeutic use
Immune Checkpoint Inhibitors pharmacology
Mice, Inbred C57BL
Biopterins analogs & derivatives
Biopterins metabolism
Female
Male
Reactive Oxygen Species metabolism
Pancreatic Neoplasms pathology
Pancreatic Neoplasms immunology
Pancreatic Neoplasms metabolism
Carcinoma, Pancreatic Ductal immunology
Carcinoma, Pancreatic Ductal pathology
Carcinoma, Pancreatic Ductal metabolism
Carcinoma, Pancreatic Ductal drug therapy
Carcinoma, Pancreatic Ductal genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1932-7420
- Volume :
- 36
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cell metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 38642552
- Full Text :
- https://doi.org/10.1016/j.cmet.2024.03.015