Single cell immune landscapes and translational models of endometriosis reveal diagnostic and therapeutic insights

Endometriosis is a chronic, inflammatory disorder characterised by the presence of extrauterine endometrial-like tissue (endometriotic lesions) within the peritoneal cavity, and is associated with severe symptoms that include chronic pelvic pain and infertility. This disorder impacts 190 million women worldwide, however, management of endometriosis is currently insufficient and there is an urgent need for novel therapeutics and non-invasive diagnostics. Macrophages are central to the pathophysiology of endometriosis, and evidence from patients and animal models has revealed that disease-modified macrophages play critical roles in the proliferation, vascularisation and innervation of lesions. Consequently, these endometriosis-associated macrophages represent promising therapeutic targets. Within the endometriotic niche, macrophage populations are either embryo-derived and self-renewing, or arise from infiltrating monocyte precursors. Similarly to macrophages, circulating monocytes can also become disease-modified by systemic inflammation and signalling from tissue microenvironments, leading to altered transcriptomic and phenotypic signatures. However, the full transcriptomic heterogeneity of macrophages and peripheral monocytes remains incompletely defined in endometriosis. I hypothesise that endometriosis-associated macrophages and monocytes comprise distinct populations with transcriptional programs that are conserved across species, some of which promote disease and can be therapeutically targeted. To test this, three aims were pursued within this thesis. First, I interrogated the translational relevance of mouse models of induced endometriosis by performing a cross-species transcriptomic alignment of macrophage populations from women with endometriosis and a mouse model of endometriosis. Second, I evaluated the therapeutic potential of macrophage reprogramming using a targeted macrophage modulating agent across multiple mouse models. Finally, I performed transcriptomic profiling of myeloid cells within the peritoneal fluid and peripheral blood from women with and without endometriosis, to identify disease associated gene signatures. This integrative approach identified conserved macrophage populations with shared, disease-promoting transcriptional programs between humans and mice, demonstrated that therapeutic macrophage modulation suppresses lesion growth and endometriosis-associated pain in a translational mouse model, and revealed endometriosis specific myeloid transcriptomic signatures in the peritoneal fluid and peripheral blood. Collectively, this thesis highlights macrophage reprogramming as a promising therapeutic strategy, provides a comprehensive, myeloid-focused investigation of endometriosis, and proposes novel avenues for both intervention and diagnosis.