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

Abstract

The secreted protein Cystatin C (CyC) is a cysteine protease inhibitor of incompletely characterized biomedical function, used clinically for estimation of glomerular filtration rate. Plasma CyC is elevated in many patients, especially when they receive glucocorticoid (GC) treatment. Here we empirically connect GCs with systemic regulation of CyC. First, we leveraged genome-wide association and structural equation modeling to determine the genetics of the latent trait CyC production in UK Biobank. Using multi-modal genomic, transcriptional, and experimental approaches, we demonstrated that CyC is a direct target of GC receptor, with GC-responsive CyC secretion exhibited by macrophages and cancer cells in vitro. Elevated serum CyC levels were positively correlated with GC levels in a murine model of cancer progression. Consistent with the coupling of CyC levels to GC signaling in a disease relevant manner, CyC predicted elevated all-cause and cancer-specific mortality in humans. These associations were orthogonally confirmed by a polygenic score (PGS) capturing germline predisposition to CyC production. This PGS predicted checkpoint immunotherapy failure in a combined clinical trial cohort of 685 metastatic cancer patients, with available germline exome sequencing. Taken together, our results demonstrate that CyC captures biomedically-relevant variations in endogenous GC activity, raising the possibility that CyC may be a direct effector of GC-induced immunosuppression and therefore a target for combination cancer immunotherapy.

Pan-cancer investigation of C-to-U editing reveals its important role in cancer development and new targets for cancer treatment

“…CST3 editing was more frequent in patients responsive to anti-PD1 during treatment. Notably, CST3 was recently reported as a glucocorticoid response gene and can predict immunotherapy failure of patients with multiple cancers, including melanoma, possibly by directing recruitment of Trem2+ macrophages ( 27 ). In cancer, CST3 has also been linked to the removal of T cells and a lack of response to blocking immune checkpoints ( 28 ).…”

DIRC3-IGFBP5 is a shared genetic risk locus and therapeutic target for carpal tunnel syndrome and trigger finger

“…We selected participants with available imputed genomic data (field 22028), and excluded participants with sex chromosome aneuploidy (field 22019), discordant genetic sex (fields 31 and 22001), excess heterozygosity and missing rate (field 22027). Classification of genetic ancestry was performed as described previously 35 , identifying 456,606 participants with >70% probability of European ancestry. Principal components (PC1-10), accounting for population structure, were computed from high-quality SNPs derived from the ‘in_PCA’ field in the UKB SNP quality control resource (‘ukb_snp_qc.txt’).…”