prostaglandin-d2 and Leukemia--Promyelocytic--Acute

Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 and NKp30 with elevated tumour-derived PGD2 and B7H6, respectively. ILC2s, in turn, activate monocytic myeloid-derived suppressor cells (M-MDSCs) via IL-13 secretion. Upon treating APL with all-trans retinoic acid and achieving complete remission, the levels of PGD2, NKp30, ILC2s, IL-13 and M-MDSCs are restored. Similarly, disruption of this tumour immunosuppressive axis by specifically blocking PGD2, IL-13 and NKp30 partially restores ILC2 and M-MDSC levels and results in increased survival. Thus, using APL as a model, we uncover a tolerogenic pathway that may represent a relevant immunosuppressive, therapeutic targetable, mechanism operating in various human tumour types, as supported by our observations in prostate cancer.Group 2 innate lymphoid cells (ILC2s) modulate inflammatory and allergic responses, but their function in cancer immunity is still unclear. Here the authors show that, in acute promyelocytic leukaemia, tumour-activated ILC2s secrete IL-13 to induce myeloid-derived suppressor cells and support tumour growth.

Topics: A549 Cells; Animals; Antineoplastic Agents; B7 Antigens; Cell Line, Tumor; Disease Models, Animal; Hep G2 Cells; HL-60 Cells; Humans; Immunity, Innate; Interleukin-13; Leukemia, Promyelocytic, Acute; Lymphocytes; Mice, Inbred C57BL; Myeloid-Derived Suppressor Cells; Natural Cytotoxicity Triggering Receptor 3; Prostaglandin D2; Protein Binding; Tretinoin

While tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising new agent for the treatment of cancer, resistance to TRAIL remains a therapeutic challenge. Identifying agents to use in combination with TRAIL to enhance apoptosis in leukemia cells would increase the potential utility of this agent as a therapy for leukemia. Here, we show that 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), a natural ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), can sensitize TRAIL-resistant leukemic HL-60 cells to TRAIL-induced apoptosis. The sensitization to TRAIL-induced apoptosis by 15d-PGJ2 was not blocked by a PPARgamma inhibitor (GW9662), suggesting a PPARgamma-independent mechanism. This process was accompanied by activation of caspase-8, caspase-9, and caspase-3 and was concomitant with Bid and PARP cleavage. We observed significant decreases in XIAP, Bcl-2, and c-FLIP after cotreatment with 15d-PGJ2 and TRAIL. We also observed the inhibition of Akt expression and phosphorylation by cotreatment with 15d-PGJ2 and TRAIL. Furthermore, inactivation of Akt by Akt inhibitor IV sensitized human leukemic HL-60 cells to TRAIL, indicating a key role for Akt inhibition in these events. Taken together, these findings indicate that 15d-PGJ2 may augment TRAIL-induced apoptosis in human leukemia cells by down-regulating the expression and phosphorylation of Akt.

Topics: Apoptosis; Down-Regulation; HL-60 Cells; Humans; Jurkat Cells; Leukemia, Promyelocytic, Acute; Phosphorylation; Prostaglandin D2; Proto-Oncogene Proteins c-akt; TNF-Related Apoptosis-Inducing Ligand

Human promyelocytic leukaemic HL-60 cells can be differentiated with DMSO to become neutrophil-like. In this study, the prostanoid receptors linked to adenylate cyclase have been compared in human neutrophils and in differentiated HL-60 cells. Both cell types appear to express EP2 receptors as recognised by the ability of EP2 agonists and not EP1 or EP3 agonists to increase cell cyclic AMP levels, and the finding that the increase in cyclic AMP induced by PGE2 was not blocked by the EP4 receptor antagonist AH 23,848 (30 microM). Neither cell type appears to express receptors for PGI2, but human neutrophils and not differentiated HL-60 cells express receptors for PGD2. In addition, human neutrophils may contain EP3 receptors linked to a reduction in cyclic AMP levels. The lack of other prostanoid receptors coupled to adenylate cyclase in HL-60 cells suggests that these cells may provide a useful starting point for the cloning of the EP2 receptor.

Topics: Adenylyl Cyclases; Cell Differentiation; Dimethyl Sulfoxide; Enzyme Activation; Humans; Leukemia, Promyelocytic, Acute; Neutrophils; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Receptors, Prostaglandin E; Tumor Cells, Cultured