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

Cystatin C (CyC) is a secreted cysteine protease inhibitor and its biological functions remain insufficiently characterized. Plasma CyC is elevated in many patients, especially when receiving glucocorticoid (GC) treatment. Endogenous GCs are essential for life and are appropriately upregulated in response to systemic stress. Here we empirically connect GCs with systemic regulation of CyC. We used genome-wide association and structural equation modeling to determine the genetics of the latent trait CyC production in UK Biobank. CyC production and a polygenic score (PGS) capturing germline predisposition to CyC production predicted elevated all-cause and cancer-specific mortality. We then demonstrated that CyC is a direct target of GC receptor, with GC-responsive CyC secretion exhibited by macrophages and cancer cells. Using isogenic CyC-knockout tumors, we discovered a markedly attenuated tumor growth in vivo and found abrogated recruitment of Trem2+ macrophages, which have been previously linked to failure of cancer immunotherapy. Finally, we showed that the CyC-production PGS predicted checkpoint immunotherapy failure in a combined clinical trial cohort of 685 metastatic cancer patients. Taken together, our results demonstrate that CyC may be a direct effector of GC-induced immunosuppression, acting through recruitment of Trem2+ macrophages, and therefore could be a target for combination cancer immunotherapy

Human Y Chromosome Exerts Pleiotropic Effects on Susceptibility to Atherosclerosis

OBJECTIVE: The male-specific region of the Y chromosome (MSY) remains one of the most unexplored regions of the genome. We sought to examine how the genetic variants of the MSY influence male susceptibility to coronary artery disease (CAD) and atherosclerosis. Approach and Results: Analysis of 129 133 men from UK Biobank revealed that only one of 7 common MSY haplogroups (haplogroup I1) was associated with CAD-carriers of haplogroup I1 had ≈11% increase in risk of CAD when compared with all other haplogroups combined (odds ratio, 1.11; 95% CI, 1.04-1.18; P=6.8×10-4). Targeted MSY sequencing uncovered 235 variants exclusive to this haplogroup. The haplogroup I1-specific variants showed 2.45- and 1.56-fold respective enrichment for promoter and enhancer chromatin states, in cells/tissues relevant to atherosclerosis, when compared with other MSY variants. Gene set enrichment analysis in CAD-relevant tissues showed that haplogroup I1 was associated with changes in pathways responsible for early and late stages of atherosclerosis development including defence against pathogens, immunity, oxidative phosphorylation, mitochondrial respiration, lipids, coagulation, and extracellular matrix remodeling. UTY was the only Y chromosome gene whose blood expression was associated with haplogroup I1. Experimental reduction of UTY expression in macrophages led to changes in expression of 59 pathways (28 of which overlapped with those associated with haplogroup I1) and a significant reduction in the immune costimulatory signal. CONCLUSIONS: Haplogroup I1 is enriched for regulatory chromatin variants in numerous cells of relevance to CAD and increases cardiovascular risk through proatherosclerotic reprogramming of the transcriptome, partly through UTY