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

Kleeman, Sam O, Thakir, Tuba Mansoor, Demestichas, Breanna, Mourikis, Nicholas, Loiero, Dominik, Ferrer, Miriam, Bankier, Sean, Riazat-Kesh, Yosef JRA, Lee, Hassal, Chantzichristos, Dimitrios, Regan, Claire, Preall, Jonathan, Sinha, Sarthak, Rosin, Nicole, Yipp, Bryan, de Almeida, Luiz GN, Biernaskie, Jeff, Dufour, Antoine, Tober-Lau, Pinkus, Ruusalepp, Arno, Bjorkegren, Johan LM, Ralser, Markus, Kurth, Florian, Demichev, Vadim, Heywood, Todd, Gao, Qing, Johannsson, Gudmundur, Koelzer, Viktor H, Walker, Brian R, Meyer, Hannah V, Janowitz, Tobias (August 2023) Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy. Cell Genomics, 3 (8). p. 100347. ISSN 2666-979X

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URL: https://www.ncbi.nlm.nih.gov/pubmed/37601967

DOI: 10.1016/j.xgen.2023.100347

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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > cancer > drugs and therapies diseases & disorders > cancer > drugs and therapies > Immunotherapy organs, tissues, organelles, cell types and functions > organs types and functions > kidney organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages organs, tissues, organelles, cell types and functions > organs types and functions organs, tissues, organelles, cell types and functions
CSHL Authors:	Kleeman, Sam Demestichas, Breanna Mourikis, Nicholas Lee, Hassal Regan, Claire Preall, Jonathan Gao, Qing Meyer, Hannah V. Janowitz, Tobias Ferrer, Miriam Thakir, Tuba
Communities:	CSHL labs > Janowitz lab CSHL labs > Meyer Lab CSHL labs > Preall lab School of Biological Sciences > Publications CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Cellular Communication in Cancer Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	9 August 2023
Date Deposited:	19 Sep 2023 20:21
Last Modified:	29 Apr 2024 19:57
PMCID:	PMC10435381
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/40926

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