Activation of Siglec-7 results in inhibition of in vitro and in vivo growth of human mast cell leukemia cells.

Advanced systemic mastocytosis is a rare and still untreatable disease. Blocking antibodies against inhibitory receptors, also known as "immune checkpoints", have revolutionized anti-cancer treatment. Inhibitory receptors are expressed not only on normal immune cells, including mast cells but also on neoplastic cells. Whether activation of inhibitory receptors through monoclonal antibodies can lead to tumor growth inhibition remains mostly unknown. Here we show that the inhibitory receptor Siglec-7 is expressed by primary neoplastic mast cells in patients with systemic mastocytosis and by mast cell leukemia cell lines. Activation of Siglec-7 by anti-Siglec-7 monoclonal antibody caused phosphorylation of Src homology region 2 domain-containing phosphatase-1 (SHP-1), reduced phosphorylation of KIT and induced growth inhibition in mast cell lines. In SCID-beige mice injected with either the human mast cell line HMC-1.1 and HMC-1.2 or with Siglec-7 transduced B cell lymphoma cells, anti-Siglec-7 monoclonal antibody reduced tumor growth by a mechanism involving Siglec-7 cytoplasmic domains in "preventive" and "treatment" settings. These data demonstrate that activation of Siglec-7 on mast cell lines can inhibit their growth in vitro and in vivo. This might pave the way to additional treatment strategies for mastocytosis.

Molecular targets on mast cells and basophils for novel therapies.

Mast cells and basophils (MCs/Bs) play a crucial role in type I allergy, as well as in innate and adaptive immune responses. These cells mediate their actions through soluble mediators, some of which are targeted therapeutically by, for example, H1- and H2-antihistamines or cysteinyl leukotriene receptor antagonists. Recently, considerable progress has been made in developing new drugs that target additional MC/B mediators or receptors, such as serine proteinases, histamine 4-receptor, 5-lipoxygenase-activating protein, 15-lipoxygenase-1, prostaglandin D2, and proinflammatory cytokines. Mediator production can be abrogated by the use of inhibitors directed against key intracellular enzymes, some of which have been used in clinical trials (eg, inhibitors of spleen tyrosine kinase, phosphatidylinositol 3-kinase, Bruton tyrosine kinase, and the protein tyrosine kinase KIT). Reduced MC/B function can also be achieved by enhancing Src homology 2 domain-containing inositol 5' phosphatase 1 activity or by blocking sphingosine-1-phosphate. Therapeutic interventions in mast cell-associated diseases potentially include drugs that either block ion channels and adhesion molecules or antagonize antiapoptotic effects on B-cell lymphoma 2 family members. MCs/Bs express high-affinity IgE receptors, and blocking their interactions with IgE has been a prime goal in antiallergic therapy. Surface-activating receptors, such as CD48 and thymic stromal lymphopoietin receptors, as well as inhibitory receptors, such as CD300a, FcγRIIb, and endocannabinoid receptors, hold promising therapeutic possibilities based on preclinical studies. The inhibition of activating receptors might help prevent allergic reactions from developing, although most of the candidate drugs are not sufficiently cell specific. In this review recent advances in the development of novel therapeutics toward different molecules of MCs/Bs are presented.

Novel identified receptors on mast cells.

Mast cells (MC) are major participants in the allergic reaction. In addition they possess immunomodulatory roles in the innate and adaptive immune reactions. Their functions are modulated through a number of activating and inhibitory receptors expressed on their surface. This review deals with some of the most recently described receptors, their expression patterns, ligand(s), signal transduction mechanisms, possible cross-talk with other receptors and, last but not least, regulatory functions that the MC can perform based on their receptor expression in health or in disease. Where the receptor role on MC is still not clear, evidences from other hematopoietic cells expressing them is provided as a possible insight for their function on MC. Suggested strategies to modulate these receptors' activity for the purpose of therapeutic intervention are also discussed.