The transcriptome of CD14 + CD163 - HLA-DR low monocytes predicts mortality in Idiopathic Pulmonary Fibrosis

Background The association between immune-cell-specific transcriptomic profiles and mortality in IPF is unknown. Methods We profiled peripheral blood mononuclear cells (PBMC) by single-cell RNA sequencing (scRNA-seq) and investigated which immune-cell-specific transcriptomic profile predicted IPF outcomes consistently. Prognostic accuracy was investigated in PBMC, Bronchoalveolar Lavage (BAL) and lung tissue. Findings were validated by flow cytometry, analysis of independent scRNA-seq datasets and cellular deconvolution. We investigated the function of this transcriptomic profile and its cellular source in lung tissue (overall sample size:1054, IPF:555, other:499). Connectivity map and LASSO regression were used to identify drug candidates and a subset of genes with prognostic potential, respectively. Results A 230-gene-up-score (Pittsburgh-PBMC) from CD14 + CD163 − HLA-DR low monocytes predicted mortality in Chicago PBMC cohort (HR: 6.58, 95%CI:2.15–20.13, p=0.001), in BAL pooled analysis (HR: 2.20, 95%CI: 1.44–3.37, p=0.0003) and negatively correlated with Forced Vital Capacity (FVC) in lung tissues (ρ=−0.2, p=0.02). CD14 + CD163 − HLA-DR low monocytes were higher in progressive versus stable IPF (12.59%, 95%CI:9.66–16.23, versus 7.61%, 95%CI:6.68–10.21, p=0.014). High risk IPF patients had decreased expression of T-cell co-stimulatory genes (Pittsburgh and Chicago p<0.01). CD14 + HLA-DR low monocytes had higher expression of profibrotic, proangiogenic and chemotactic factors compared to CD14 + HLA-DR hi monocytes (p<0.05). The 230-gene-up-score correlated with the SPP1 + fibrosis-associated macrophages-gene-score in lung tissues (ρ=0.19, p<2.2e − 16). Connectivity map identified drug categories to reverse the 230-gene-signature. A subset of six genes retained predictive performance (pooled PBMC cohorts -HR: 4.79, 95%CI:2.58–8.92, p<0.0001). Conclusions The transcriptome of CD14 + CD163 − HLA-DR low monocytes is associated with increased mortality in patients with IPF. Its reversal should be investigated as a precision-based therapy in IPF.