Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Distinct mechanisms of dysfunctional antigen-presenting DCs and monocytes by single-cell sequencing in multiple myeloma.

Abstract

Multiple myeloma (MM) is an incurable plasma cell malignancy with the hallmark of immunodeficiency, including dysfunction of T cells, NK cells and antigen presentation cells (APC). Dysfunctional APCs have been reported to play a key role in promoting MM progression. However, the molecular mechanisms remain elusive. Here, single-cell transcriptome analysis of dendritic cells (DC) and monocytes from 10 MM patients and 3 healthy volunteers was performed. Both DCs and monocytes were divided into 5 distinct clusters respectively. Among them, monocyte-derived DC (mono-DC) was shown to develop from intermediate monocyte (IM) via trajectory analysis. Functional analysis showed that compared with healthy controls, conventional DC2 (cDC2), mono-DC and IM of MM patients exhibited impaired antigen processing and presentation capacity. Moreover, reduced regulon activity of interferon regulatory factor 1 (IRF1) was found in cDC2, mono-DC and IM of MM patients according to SCENIC analysis, while the downstream mechanisms were distinct. Specifically in MM patients, cathepsin S (CTSS) was remarkably downregulated in cDC2, MHC class II transactivator (CIITA) was significantly decreased in IM, meanwhile both CTSS and CIITA were downregulated in mono-DC based on DEG analysis. In vitro study validated that knockdown of Irf1 downregulated Ctss and Ciita respectively in mouse DC cell line DC2.4 and mouse monocyte/macrophage cell line RAW264.7, which ultimately inhibited proliferation of CD4+ T cells after being cocultured with DC2.4 or RAW264.7 cells. The current study unveils the distinct mechanisms of cDC2, IM and mono-DC function impairment in MM, offering a new insight into the pathogenesis of immunodeficiency.