Inflammatory, Functional, and Compositional Changes of the Uterine Immune Microenvironment in a...

Lymphangioleiomyomatosis (LAM) is a rare, female-dominated pulmonary cystic disease. Cysts that develop in LAM are characterized by the presence of smooth muscle-like (LAMCore) cells in the periphery. These cells harbor mutations in Tuberous Sclerosis Complex 1 or 2 (TSC1/2), driving uncontrolled proliferation through the mTORC1 pathway. LAMCore cells originate from an extrapulmonary source. Published data supports the uterine origin of LAMCore cells that metastasize from the uterus to precipitate pulmonary function destruction. Immune evasion is hypothesized to occur to allow seeding of the lungs from the uterus. This evasion specifically involves dysfunctional NK cells to allow aberrant proliferation and migration from the tissue. Single-cell RNA sequencing revealed changes in chemokine and cytokine protein and receptor expression in uterine NK (uNK) and other immune cell populations in a uterine-specific Tsc2-knockout mouse model of LAM. ELISA data revealed increased concentrations of multiple pro-inflammatory cytokines in the sera of aged Tsc2-knockout mice. Flow cytometry, IHC, and functional assays identified compositional and functional insufficiencies of the uNK cells in Tsc2-knockout mice. Furthermore, depletion of NK cells led to the increased development of pulmonary metastases. These data suggest an inflammatory feedback loop affecting multiple cell types including uNK cells, macrophages, and neutrophils. This leads to alterations in immune cell function and composition which allow for LAMCore cell metastasis from the uterine tissue, which may provide a novel mechanism for LAM development.