Mesenchymal PGD(2) activates an ILC2-Treg axis to promote proliferation of normal and malignant HSPCs

Cyclooxygenase (COX)-dependent production of prostaglandins (PGs) is known to play important roles in tumorigenesis. PGD(2) has recently emerged as a key regulator of tumor- and inflammation-associated functions. Here we show that mesenchymal stromal cells (MSCs) from patients with acute myeloid leukemia (AML) or normal MSCs overexpressing COX2 promote proliferation of co-cultured hematopoietic stem and progenitor cells (HSPCs), which can be prevented by treatment with COX2 knockdown or TM30089, a specific antagonist of the PGD(2) receptor CRTH2. Mechanistically, we demonstrate that PGD(2)-CRTH2 signaling acts directly on type 2 innate lymphoid cells (ILC2s), potentiating their expansion and driving them to produce Interleukin-5 (IL-5) and IL-13. Furthermore, IL-5 but not IL-13 expands CD4(+)CD25(+)IL5Rα(+) T regulatory cells (Tregs) and promotes HSPC proliferation. Disruption of the PGD(2)-activated ILC2-Treg axis by specifically blocking the PGD(2) receptor CRTH2 or IL-5 impedes proliferation of normal and malignant HSPCs. Conversely, co-transfer of CD4(+)CD25(+)IL5Rα(+) Tregs promotes malignant HSPC proliferation and accelerates leukemia development in xenotransplanted mice. Collectively, these results indicate that the mesenchymal source of PGD(2) promotes proliferation of normal and malignant HSPCs through activation of the ILC2-Treg axis. These findings also suggest that this novel PGD(2)-activated ILC2-Treg axis may be a valuable therapeutic target for cancer and inflammation-associated diseases.