ABSTRACT
A hallmark of bone marrow changes with aging is the increase in adipocyte composition, but how this impacts development of multiple myeloma (MM) is unknown. Here, we report the role of the adipokine leptin as master regulator of anti-myeloma tumor immunity by modulating the invariant natural killer T (iNKT) cell function. A marked increase in serum leptin levels and leptin receptor (LR) expression on iNKT cells in MM patients and the 5T33 murine MM model was observed. MM cells and leptin synergistically counteracted anti-tumor functionality of both murine and human iNKT cells. In vivo blockade of LR signaling combined with iNKT stimulation resulted in superior anti-tumor protection. This was linked to persistent IFN-γ secretion upon repeated iNKT cell stimulation and a restoration of the dynamic antigen-induced motility arrest as observed by intravital microscopy, thereby showing alleviation of iNKT cell anergy. Overall our data reveal the LR axis as novel therapeutic target for checkpoint inhibition to treat MM.
Subject(s)
Antineoplastic Agents/pharmacology , Multiple Myeloma/metabolism , Natural Killer T-Cells/drug effects , Natural Killer T-Cells/metabolism , Receptors, Leptin/antagonists & inhibitors , Animals , Antibodies, Monoclonal , Cell Line, Tumor , Cell Proliferation/drug effects , Cytokines/biosynthesis , Disease Models, Animal , Galactosylceramides/pharmacology , Humans , Leptin/metabolism , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Mice , Mice, Knockout , Molecular Targeted Therapy , Multiple Myeloma/drug therapy , Multiple Myeloma/immunology , Natural Killer T-Cells/immunology , Xenograft Model Antitumor AssaysABSTRACT
The pivotal role of leptin in regulating body weight and energy homeostasis is very well established. More recently, leptin also emerged as an important regulator of T-cell-dependent immunity. Reduced leptin levels, as observed during periods of starvation, correlate with an impaired cellular immune response, whereby especially the T(H)1 pro-inflammatory immune response appears to be affected. Physiologically, this could reflect the high energy demand of such processes, which are suppressed in animals or people with nutrient shortage. Several autoimmune diseases are T(H)1 T-cell dependent. In line with a pro-inflammatory role for leptin, animal models of leptin deficiency are markedly resistant to a variety of T-cell dependent autoimmune diseases. Here, we review the role of leptin in immune responses, with emphasis on autoimmune diseases. The design and potential use of leptin antagonists is also discussed.
Subject(s)
Autoimmune Diseases/drug therapy , Leptin/antagonists & inhibitors , Leptin/immunology , Animals , Antibody Formation/immunology , Autoimmune Diseases/immunology , HumansABSTRACT
Leptin was originally discovered as an adipocyte-derived hormone involved in the central control of body weight and energy homeostasis. It is now clear that leptin is a pleiotropic cytokine, with activities on many peripheral cell types. These findings may help explain the surprising role of leptin in pathophysiological processes. Recent evidence suggests that leptin contributes to atherosclerosis and to the increased risk of cardiovascular disease in obese people. Leptin also appears to be involved in T-cell-dependent immunity and possibly in the development and maintenance of certain autoimmune diseases. Here, we review the role of leptin in cardiovascular and autoimmune diseases, and also briefly address the potential therapeutic use of leptin antagonists.
Subject(s)
Adipocytes/metabolism , Autoimmune Diseases/metabolism , Cardiovascular Diseases/metabolism , Leptin/metabolism , Arteriosclerosis/etiology , Arteriosclerosis/metabolism , Autoimmune Diseases/etiology , Cardiovascular Diseases/etiology , Humans , Immunity, Cellular/physiology , Insulin Resistance/physiology , Leptin/antagonists & inhibitors , Receptors, Leptin , Receptors, Mitogen/metabolism , Signal Transduction/physiologyABSTRACT
IL-5 is a major determinant in the survival, differentiation and effector-functions of eosinophils. It mediates its effect upon binding and activation of a membrane bound receptor (R), composed of a ligand-specific alpha-chain and a beta-chain, shared with the receptors for IL-3 and granulocyte-macrophage colony-stimulating factor. We have generated and mapped the epitopes of three monoclonal antibodies (mAb) directed against this cytokine: the strong neutralizing mAb 5A5 and 1E1, and the very weak neutralizing mAb H30. We found that H30 as well as 5A5 can increase proliferation above the level induced by human (h)IL-5 alone, in a JAK-2-dependent manner, and at every sub-optimal hIL-5 concentration analyzed. This effect is dependent on mAb-mediated cross-linking of IL-5R complexes, and is only observed on cell lines expressing a hybrid human/mouse IL-5Ralpha-chain. We discuss these findings in view of the stoichiometric and topological requirements for an activated IL-5R. Since humanized anti-IL-5 mAb are currently in clinical testing, our findings imply that such mAb should be carefully evaluated for their potentiating effects.
