Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy.
GWAS
PGS
cystatin C
glucocorticoids
immunotherapy
macrophages
renal function
Journal
Cell genomics
ISSN: 2666-979X
Titre abrégé: Cell Genom
Pays: United States
ID NLM: 9918284260106676
Informations de publication
Date de publication:
09 Aug 2023
09 Aug 2023
Historique:
received:
13
06
2022
revised:
23
03
2023
accepted:
30
05
2023
medline:
21
8
2023
pubmed:
21
8
2023
entrez:
21
8
2023
Statut:
epublish
Résumé
Cystatin C (CyC), a secreted cysteine protease inhibitor, has unclear biological functions. Many patients exhibit elevated plasma CyC levels, particularly during glucocorticoid (GC) treatment. This study links GCs with CyC's systemic regulation by utilizing genome-wide association and structural equation modeling to determine CyC production genetics in the UK Biobank. Both CyC production and a polygenic score (PGS) capturing predisposition to CyC production were associated with increased all-cause and cancer-specific mortality. We found that the GC receptor directly targets CyC, leading to GC-responsive CyC secretion in macrophages and cancer cells. CyC-knockout tumors displayed significantly reduced growth and diminished recruitment of TREM2+ macrophages, which have been connected to cancer immunotherapy failure. Furthermore, the CyC-production PGS predicted checkpoint immunotherapy failure in 685 patients with metastatic cancer from combined clinical trial cohorts. In conclusion, CyC may act as a GC effector pathway via TREM2+ macrophage recruitment and may be a potential target for combination cancer immunotherapy.
Identifiants
pubmed: 37601967
doi: 10.1016/j.xgen.2023.100347
pii: S2666-979X(23)00122-2
pmc: PMC10435381
doi:
Banques de données
figshare
['10.6084/m9.figshare.14330795.v13']
Types de publication
Journal Article
Langues
eng
Pagination
100347Informations de copyright
© 2023.
Déclaration de conflit d'intérêts
The authors declare no competing interests.
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