Human myeloid cells in cancer, inflammation, and infection

Abstract

Myeloid cells are a part of innate immunity, playing a major role in orchestrating innate and adaptive immune responses. While work performed in experiment model systems has significantly increased our knowledge on fundamental myeloid cell functions, studies in well-designed clinical cohorts are important for understanding their functions in human health and disease, such as in cancer, infection and chronic inflammation. In this thesis, distinct populations of human myeloid cells were investigated in three different clinical contexts: Langerhans cell histiocytosis (LCH), an inflammatory myeloid neoplasia; inflammatory bowel disease (IBD), a chronic disorder of the gastrointestinal tract; and COVID-19, an acute viral infection.

We found that neutrophils, rather than antigen presenting mononuclear phagocytes (MNPs) such as monocytes and dendritic cells (DC), are the main cellular source of the regulatory cytokine IL-23 in colon tissue of newly diagnosed and treatment-naïve children with IBD (paper I). Moreover, we demonstrated that inflammation-responsive intestinal stroma has a capacity to shape the monocyte-derived macrophage pool, and that phenotypes modelled in fibroblast-macrophage co-culture systems were reflected in the IBD tissue (paper II). In addition, while the role of IL-23 is well-established in IBD, we also proposed its potential involvement in the immunopathogenesis of LCH (paper III). Furthermore, proficient delineation of LCH cells, that are neoplastic MNP found in LCH lesions, from the normal MNPs was performed at single-cell resolution, allowing identification of two major LCH cell populations, corresponding to DC type 2 and monocytes/DC type 3 lineages (paper IV). Lastly, a comprehensive map over major alterations in MNP responses in COVID-19 was depicted, where MNPs profile, alone, could predict a cluster of non-survivors (paper V).

Taken together, this data provides important input in our understanding of the role of MNPs in human disease, also showing that we only scratch the surface of myeloid cell functions in cancer, inflammation, and infection, as many outstanding questions remain.