Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and deadly fibrotic lung disease. Myeloid-derived suppressor cells (MDSC) are pathologically activated immature myeloid cells, which suppress immune responses in cancer, autoimmunity, and other conditions. Recent literature supports that aberrant immune responses contribute to IPF pathogenesis. We reported, for the first time, that MDSC are increased in numbers, functionally active, and reflect disease status in IPF, in cross-sectional and longitudinal analysis serving as potent biomarker for IPF progression. Monocytic MDSC are the predominant subtype in IPF, and yet, differences between mature monocytes and monocytic MDSC, and their interaction in IPF have not been explored.

In this study, we included 170 patients, including patients with IPF (n=69), non-IPF ILD (n=56), COPD (n=23), and controls (n=22). We explore for the first time the MDSC proteome in fibrosis. We detected an increase in MDSC in peripheral blood from IPF patients. We further detected a correlation between MDSC and FoxP3+ T cells, and a decrease in the transcript levels of CD28, ICOS, ITK, and LCK in PBMC of IPF patients, suggesting that elevated MDSC might cause a blunted immune response.  Using network analysis, our proteome data shows an autocrine and paracrine signals from and between monocytes and MDSC. MDSC signals include strong pro-fibrotic molecules (COL1A1, FN1, HLA-C, HSPG2, MMP1, S100A8-9, TGFB1), supporting a pro-fibrotic role. Furthermore, confirmation by flow cytometry of exclusively expressed surface receptors, might lead to identification of novel proteins useful for therapeutic targeting of MDSC and monocytes in IPF.