Background: Idiopathic Pulmonary Fibrosis (IPF) is a heterogeneous disease. Currently, its diagnosis and treatment is driven by their clinical signs and symptoms, instead of by the underlying biological mechanisms (endotypes).

Objectives: To determine the relation between the type and magnitude of the lung immune response with specific endotypes and pathological features.

Methods: The lung immune response was characterized applying immune deconvolution methods (GSVA) to transcriptomic data (n=109). Main results were validated in two independent sets; n=26 from the University of Pittsburgh and n=13 from the CIBERES biobank.

Results: IPF lung samples were split in two clusters, differing in the type and level of immune infiltration. Being mostly different in cytotoxic (0.29 vs. -0.38, p=2.68·10-18) and B cell (0.19 vs. -0.26, p=2.08·10-9) levels. These observations were reproduced in two independent sets of IPF samples using different methods; RT-qPCR and flow cytometry. There were no differences in fibrosis or cell cycle related signatures between clusters, but the cluster with lower immune expression was enriched in ciliated and secretory epithelial cells gene signatures (p-value 2.68·10-10 and 1.28·10-6). Interestingly, only in this cluster the epithelial signature had a positive correlation with the IPF associated CT scan values and negative with the lung function test (FVC).

Conclusions: The type of lung immune infiltrate defines two groups of IPF patients or endotypes, which in turn are associated with different pathological features. This study opens a new perspective on the potential role of the immune response as a main driver of IPF heterogeneity.