Idiopathic pulmonary fibrosis (IPF) remains a clinical challenge with several unmet needs. Evidences support monocytes as biomarkers of IPF progression. Yet, specific myeloid subtypes and their role in disease are unknown.

Using multi-color flow cytometry, we analyzed the abundance of circulating myeloid subsets. We confirmed increases in classical monocytes and immunosuppressive myeloid cells, so called myeloid-derived suppressor cells (MDSC), in blood of IPF patients. To address whether MDSC suppression contributes to fibrosis, we co-cultured autologous MDSC with T cells to assess proliferation, exhaustion and Treg formation, which showed decreased proliferation of CD8+ and CD4+ T cells in IPF. We developed an in vitro model to assess exhaustion. Autologous co-cultures induced CD8+ T cell exhaustion (PD1, Lag3, Tim3, TNF?, INF?), and de-novo Treg formation. We applied single-cell transcriptomics in magnetically-purified monocyte populations to dissect the circulating heterogeneity. We detected two CD14+ monocyte states enriched in publicly available MDSC gene signatures, further supporting the presence of circulating myeloid populations with immunosuppressive features in IPF. To address whether MDSC migrate into the lung, we performed 3D gel invasion assays confirming their invasiveness potential in IPF when compared to controls. Analysis of IPF atlas confirmed the presence of exhausted CD8+ T cells in IPF tissue. Taken together, immature suppressive monocytic subsets are expanded in the peripheral blood of IPF patients and induce an immunosuppressive environment. Further studies will determine their role in disease progression and therapeutic targetability.