Modulation of infiltrating CD206-positive macrophages restricts progression of pulmonary lymphangioleiomyomatosis (LAM)
Lymphangioleiomyomatosis (LAM) is a progressive neoplastic interstitial lung disease that primarily affects women of reproductive age. It is characterized by the infiltration of the lungs by atypical "LAM" cells, which leads to the cystic destruction of lung tissue. In our study, we employed spatial transcriptomics to analyze cell populations within LAM in order to understand the significance of the spatial organization of LAM cells and macrophages. Each Visium spot covers from one to ten cells. We discovered that some spots have highly expressed macrophage-associated genes (defined as Macro:only) and some highly expressed LAM-associated genes (defined as LAM:only). There are also some spots that have highly expressed both macrophage and LAM markers; we defined these as the LAM_Macro interaction spots. To further understand the spatial organization of LAM and macrophages, we extracted all spots expressing LAM and macrophage-associated genes in our data and examined the molecular profile. In our analysis of PMEL-positive LAM samples, we observed that genes associated with macrophage homing (specifically CCL2, CSF1, CSF2, CXCL12, and IL7) are highly expressed in the LAM:Macro interaction spots. Immunofluorescence analyses showed that CD206+ macrophages are in close proximity to LAM cells in LAM patient lungs. Targeting M2 macrophages via treatment with the CD206 modulator RP-182 impaired the growth of TSC2-deficient tumors in vivo. In conclusion, M2-like CD206high macrophages may represent a potential therapeutic target in LAM. Overall design: Eight human pulmonary lymphangioleiomyomatosis (LAM) areas from four LAM patients were analyzed using 10x Visium spatial transcriptomics.