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

• DOI: 10.1016/j.xgen.2023.100347
• Publication Date: 2023-06-25T03:44:34Z
• Authors: Sam O. Kleeman; Tuba Mansoor Thakir; Breanna Demestichas; Nicholas Mourikis; Dominik Loiero; Miriam Ferrer; Sean Bankier; Yosef J.R.A. Riaz...; Hassal Lee; Dimitrios Chantzi...; 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. Bjorke...; Markus Ralser; Florian Kurth; Vadim Demichev; Todd Heywood; Qing Gao; Gudmundur Johannsson; Viktor H. Koelzer; Brian R. Walker; Hannah V. Meyer; Tobias Janowitz
• Keywords: Cancer Immunotherapy; Cystatin

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 production genetics in the UK Biobank. Both polygenic score (PGS) capturing predisposition were associated increased all-cause cancer-specific mortality. We found that GC receptor directly targets CyC, leading GC-responsive secretion macrophages cancer cells. CyC-knockout tumors displayed significantly reduced growth diminished recruitment of TREM2+ macrophages, which have been connected immunotherapy failure. Furthermore, CyC-production PGS predicted checkpoint failure 685 metastatic from combined clinical trial cohorts. In conclusion, may act as effector pathway via macrophage be potential target for combination immunotherapy.