Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy

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 structura...

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Published in:	Cell genomics Vol. 3; no. 8; p. 100347
Main Authors:	Kleeman, Sam O, Thakir, Tuba Mansoor, Demestichas, Breanna, Mourikis, Nicholas, Loiero, Dominik, Ferrer, Miriam, Bankier, Sean, Riazat-Kesh, Yosef J R A, Lee, Hassal, Chantzichristos, Dimitrios, Regan, Claire, Preall, Jonathan, Sinha, Sarthak, Rosin, Nicole, Yipp, Bryan, de Almeida, Luiz G N, Biernaskie, Jeff, Dufour, Antoine, Tober-Lau, Pinkus, Ruusalepp, Arno, Bjorkegren, Johan L M, Ralser, Markus, Kurth, Florian, Demichev, Vadim, Heywood, Todd, Gao, Qing, Johannsson, Gudmundur, Koelzer, Viktor H, Walker, Brian R, Meyer, Hannah V, Janowitz, Tobias
Format:	Journal Article
Language:	English
Published:	United States Elsevier 09-08-2023
Subjects:	Cancer and Oncology Cancer och onkologi Cell and Molecular Biology Cell- och molekylärbiologi Endocrinology and Diabetes Endokrinologi och diabetes Medicin och hälsovetenskap cystatin C macrophages GWAS immunotherapy renal function glucocorticoids PGS
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally Lead contact
ISSN:	2666-979X 2666-979X
DOI:	10.1016/j.xgen.2023.100347