The human myeloid VERSE: MoMac-VERSE and DC-VERSE

Mononuclear phagocytes (MNPs), including dendritic cells, monocytes, and macrophages (MoMac), perform essential antimicrobial, homeostatic, and immunoregulatory roles. To better understand their diversity and functions, we integrated 178,651 MNPs from 13 tissues across 41 datasets, resulting in the creation of a comprehensive MNP single-cell RNA compendium (MNP-VERSE). This publicly available resource provides a detailed mapping of MNPs and defines conserved gene signatures for different MNP populations.

Building upon this, we developed a MoMac-focused compendium, uncovering a variety of specialized MoMac subsets distributed across multiple tissues. Notably, we observed that certain pathological forms, especially those associated with cancer and inflammation, showed significant expansion. We identified conserved tumor-associated macrophage populations across all neoplastic tissues. A key focus was on IL4I1+CD274(PD-L1)+IDO1+ macrophages, which were predominantly found at the tumor periphery. These macrophages accumulated in a T cell-dependent manner, influenced by interferon-γ (IFN-γ) and CD40/CD40L signaling, which triggered their maturation from IFN-primed monocytes.

IL4I1+ macrophages exhibited immunosuppressive properties through tryptophan degradation and facilitated the recruitment of regulatory T cells (Tregs) into the tumor microenvironment, further promoting immune evasion. This integrated analysis provides a robust, publicly available platform for uniform annotation and dissection of macrophage functions in both healthy and pathological conditions, offering valuable insights for further therapeutic strategies targeting MNPs in disease contexts.

Following our in-depth multi-omic analysis of tumour MoMac, we have recently generated a comprehensive and unbiased atlas of myelDC by integrating 38,293 DC from 13 tissues across 40 datasets to generate a DC single-cell RNA compendium (DC-VERSE). Dendritic cells (DCs) are professional antigen presenting cells (APCs). While plasmacytoid DCs (pDCs) are poor APCs at steady state, myeloid progenitor-derived DCs (mDCs) comprise DC1s, DC2s and DC3s, and are specialized in T-cell priming. We characterized mDC subsets and “states” across tissues and found that most studied tumours contained CD207+ mDCs that were expanded and highly proliferating in all carcinomas in which they were detected. Their expansion inversely correlated with tumour CD8+ resident memory T-cells (TRMs), T-cell clonality and survival of patients that received immune checkpoint blockade treatment.