Lymphangioleiomyomatosis: where endocrinology, immunology and tumor biology meet

Abstract

Lymphangioleiomyomatosis (LAM) is a cystic lung disease found almost exclusively in genetic females and caused by small clusters of smooth muscle cell tumors containing mutations in one of the two tuberous sclerosis genes (TSC1 or TSC2). Significant advances over the past 2-3 decades have allowed researchers and clinicians to more clearly understand the pathophysiology of LAM, and therefore better diagnose and treat patients with this disease. Despite substantial progress, only one proven treatment for LAM is used in practice: mechanistic target of rapamycin complex 1 (mTORC1) inhibition with medications such as sirolimus. While mTORC1 inhibition effectively slows LAM progression in many patients, it is not curative, is not effective in all patients, and can be associated with significant side effects. Furthermore, the presence of established and accurate biomarkers to follow LAM progression is limited. That said, discovering additional diagnostic and treatment options for LAM is paramount. This review will describe recent advances in LAM research, centering on the origin and nature of the LAM cell, the role of estrogen in LAM progression, the significance of melanocytic marker expression in LAM cells, and the potential roles of the microenvironment in promoting LAM tumor growth. By appreciating these processes in more detail, researchers and caregivers may be afforded novel approaches to aid in the treatment of patients with LAM.

Keywords: estradiol; immune microenvironment; lymphangioleiomyomatosis; melanocytic marker.

Figure 1.. Melanocytic markers in the LAM tumor microenvironment.

Highlighting the LAM cell and melanocytic marker expression and interactions, (A) MITF is a master regulator of melanocytic marker expression and acts as a transcription factor to transcribe other melanocytic marker genes such as GPNMB. TFEB is increased in TSC-null LAM cells and can similarly drive transcription of melanocytic markers. Here GPNMB is shown to be expressed both intracellularly and on the cell membrane, and its ectodomain can be cleaved off the cell surface. (B) GPNMB in its soluble or membrane bound form can interact with other LAM cells to potentially increase metastasis. (C) Soluble GPNMB or GPNMB expressed on immunosuppressive monocytes can interact with Syndecan-4 to suppress T cell function.

Figure 2.. LAM tumor immune microenvironment consists of potential therapeutic targets.

Comprehensive analysis of LAM lungs isolated from patients using single cell RNA sequencing demonstrates an immunologically diverse microenvironment consisting of LAM-associated fibroblasts (LAFs), monocytes, macrophages (including pre, alveolar, and interstitial macrophages), dendritic cells, B cells (including plasma cells), CD4⁺ T cells, CD8⁺ T cells, T regulatory cells (Tregs), natural killer (NK) cells, mast cells, and neutrophils. Use of human LAM samples and various pre-clinical models have identified potential immune cell-related targets to either combat the immunosuppression or direct promotion of tumor growth mediated by the noted immune cells.