Background: Tumor-associated macrophages (TAMs) promote tumorigenesis and tumor growth. They share features with profibrotic macrophages found in lung fibrosis. Identifying specific markers to target these cells in both animal and human models is complex but necessary. This proposal aimed to identify macrophage membrane receptors to link human diseases and animal/cellular models.

Methods and Results: To determine a shared gene signature unique to TAMs and profibrotic macrophages, we used transcriptomic datasets of macrophage phenotypes from both human (PBMCs) and murine (bone marrow-derived macrophages) systems obtained from the Gene Expression Omnibus database. To validate the in silico results, we conducted our own macrophage polarizations studies in vitro and utilized nanoString® technology. Through this process, 6 genes were significantly upregulated in profibrotic macrophages and were consistent in both human and murine systems. CLEC7A was one of the identified genes encoding the membrane receptor Dectin-1. In single-cell RNA-seq idiopathic pulmonary fibrosis (IPF) datasets, CLEC7A was observed to be significantly upregulated in monocytes and macrophages of IPF patients. Similarly, in a lung cancer CosMX spatial dataset, elevated expression of CLEC7A was found in TAMs. Immunohistochemical examination of lung specimens from patients with lung adenocarcinoma and IPF revealed that macrophages infiltrating fibrotic lesions and tumors had increased Dectin-1 levels. 

Conclusion: Dectin-1 is a macrophage receptor that is upregulated in both murine and human models of lung cancer and IPF serving as a potential therapeutic target to reprogram pathological macrophages.