Targeting pathological immune tolerance in endometriosis

Endometriosis is a debilitating disorder that affects 10% women of reproductive age. It is characterised by the presence of endometrial-like tissues at ectopic sites, most prominently the pelvis. Immune tolerance, neo-angiogenesis, and fibrosis of endometriotic implants lead to severe pelvic disease, causing pain, infertility, or both. It is widely accepted that retrograde seeding of endometrial cells at menstruation initiates endometriosis. However, retrograde menstruation is a common phenomenon, raising the question why some but not all women of reproductive age develop the disease. Menstruation is triggered by falling progesterone levels following decidualization (differentiation) of stromal cells in cycling endometrium. A hallmark of decidualization is progesterone-dependent repression of type I interferon, a key component of innate immunity. We hypothesize that de-repression of this pathway in response to falling progesterone levels prior to menstruation renders endometrial cells intrinsically immunogenic, resulting in rapid clearance at ectopic sites. Conversely, we postulate that menstruation-like bleeding not associated with spontaneous decidualization (i.e., breakthrough and anovulatory bleeds) leads to seeding of cells devoid of type I interferon and poised to evade immune surveillance. In other words, formation of endometriotic lesions likely depends on endometrial cell states at seeding. Testing this novel hypothesis requires a multipronged approach, including (i) bioinformatic analysis of the type I interferon pathway in human endometrium using existing single-cell RNA/ATAC and spatial transcriptomics data sets, (ii) molecular and cellular analyses of the mechanisms underpinning reciprocal repression of type I interferon and progesterone pathways, and (iii) analysis of type I interferon-dependent endometrial-immune cell interactions using co-culture systems. If validated, therapeutic strategies to enhance immune recognition of lesions will be explored.