Estradiol Induces Neutrophil Expansion to Promote TSC-Null Tumor Progression.

Emerging research reports are providing evidence on how estrogens induce aberrant hematopoiesis in bone marrow, with expansion of myeloid-derived suppressor cells to promote lymphangioleiomyomatosis (LAM) tumor progression. LAM is a multisystem disorder that occurs almost exclusively in women. This disease is characterized by proliferating, atypical smooth muscle-like cells that invade the lung to cause cystic destruction and respiratory failure (Minor BMN et al., 2023). LAM is caused by inactivating mutations in either TSC1 or TSC2 genes, leading to constitutive activation of mTOR complex 1 (mTORC1), and clinical studies indicate that LAM progression is estrogen-dependent. The mTOR inhibitor rapamycin is approved to treat patients with LAM, and this drug slows progression of respiratory impairment but is largely tumoristatic. Hence, there remains a critical need for more effective therapies. Minor and colleagues address this need in reports of a new murine model of TSC-null tumors in which estradiol-induced lung colonization of these LAM cells was found to be dependent on hormonal stimulation of granulopoiesis and neutrophil expansion in the LAM tumor microenvironment (TME). Of note, ER-alpha (ERα) is known to be expressed in early hematopoietic stem and progenitor cells in bone marrow as well as in common lymphoid and myeloid lineage progenitors. These latter cells, termed either polymorphonuclear (PMN) myeloid-derived suppressor cells (MDSCs) or neutrophils are thought to develop from hematopoietic progenitors as part of the myeloid cell lineage. Mouse PMN-MDSCs cannot be separated from mature neutrophils, and both terms are used to refer to immature myeloid cells expressing CD11b+Ly6CloLy6G+ biomarkers. In humans, PMN-MDSCs and neutrophils also share similar surface markers. The hallmark feature of MDSCs is their suppressive effect on T-cells, natural killer cells, and other antitumor defenses. This activity is detrimental, as it helps tumors establish an immunocompromised TME and escape adaptive immune responses. Further, increases in MDSCs in tumor and lymphoid tissues and peripheral blood are found to correlate with decreased overall survival in patients with different cancer types. Recent studies show that these MDSCs express ERα and that estradiol signaling promotes expansion of these cells in several preclinical tumor models. Notably, estrogen depletion and/or use of selective estrogen receptor down-regulators reduced tumor progression by decreasing MDSCs and associated pro-tumorigenic effects regardless of the ER status of the tumor itself. In the case of LAM metastasis, estradiol-enhanced lung colonization of LAM cells is dependent on neutrophils in the TME. Notably, estradiol treatment induces granulopoiesis via ER in male and female bone marrow cell cultures. Factors released from LAM mouse myometrial cells then drive estradiol-sensitive neutrophil production. In addition, single-cell RNA sequencing data from LAM patients affirm the presence of tumor-activated neutrophils in LAM specimens. Overall, the findings suggest a significant positive feedback loop whereby estradiol and tumor factors induce neutrophil expansion, which in turn intensifies LAM tumor growth and production of neutrophil-stimulating factors, resulting in continued TSC2-null tumor growth. These findings may well lead to new advances in the future management of LAM tumors in the clinic as well as other immune diseases and cancers.