| Title: | Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy |
| Journal: | Cell Genomics |
| Published: | 23 Jun 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37601967/ |
| DOI: | https://doi.org/10.1016/j.xgen.2023.100347 |
| URL: | https://ars.els-cdn.com/content/image/1-s2.0-S2666979X23001222-fx1_lrg.jpg |
| Citations: | 4 (4 in last 2 years) as of 8 Aug 2024 |
Publication 7782
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Abstract
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.</p>
31 Authors
- Sam O Kleeman
- Tuba Mansoor Thakir
- Breanna Demestichas
- Nicholas Mourikis
- Dominik Loiero
- Miriam Ferrer
- Sean Bankier
- Yosef J R A Riazat-Kesh
- Hassal Lee
- Dimitrios Chantzichristos
- Claire Regan
- Jonathan Preall
- Sarthak Sinha
- Nicole Rosin
- Bryan Yipp
- Luiz G N de Almeida
- Jeff Biernaskie
- Antoine Dufour
- Pinkus Tober-Lau
- Arno Ruusalepp
- Johan L M Bjorkegren
- Markus Ralser
- Florian Kurth
- Vadim Demichev
- Todd Heywood
- Qing Gao
- Gudmundur Johannsson
- Viktor H Koelzer
- Brian R Walker
- Hannah V Meyer
- Tobias Janowitz
1 Application
| Application ID | Title |
|---|---|
| 58510 | Modelling organ function in health and disease |
Enabling scientific discoveries that improve human health