Histamine Promotes the Development of Monocyte-Derived Dendritic Cells and Reduces Tumor Growth by Targeting the Myeloid NADPH Oxidase

Abstract

The efficiency of immune-mediated clearance of cancer cells is hampered by immunosuppressive mediators in the malignant microenvironment, including NADPH oxidase–derived reactive oxygen species. We aimed at defining the effects of histamine, an inhibitor of the myeloid NADPH oxidase/NOX2, on the development of Ag-presenting dendritic cells (DCs) from myeloid precursors and the impact of these mechanisms for tumor growth. Histamine was found to promote the maturation of human DCs from monocytes by increasing the expression of HLA-DR and costimulatory molecules, which resulted in improved induction of Th cells with Th0 polarity. Experiments using wild-type and NOX2-deficient myelomonoblastic cells showed that histamine facilitated myeloid cell maturation only in cells capable of generating reactive oxygen species. Treatment of mice with histamine reduced the growth of murine EL-4 lymphomas in parallel with an increment of tumor-infiltrating DCs in NOX2-sufficient mice but not in NOX2-deficient (gp91phox−/−) mice. We propose that strategies to target the myeloid NADPH oxidase may facilitate the development of endogenous DCs in cancer.

Killer Immunoglobulin-Like Receptor 2DL4 (CD158d) Regulates Human Mast Cells both Positively and Negatively: Possible Roles in Pregnancy and Cancer Metastasis

“…Mast-cell-produced IL-9 were shown to inhibit tumor cell engraftment [92]. Mast cells are a major source of histamine, and histamine was shown to inhibit tumor growth by promoting the development of monocyte-derived DCs [93]. The combined deficiency in mast cell chymase, tryptase, and carboxypeptidase A3 was associated with reduced invariant NKT cells and increased melanoma dissemination [94].…”

Histamine receptors and cancer pharmacology: an update

“…() further highlight the involvement of histamine in lymphoma progression. Histamine treatment induced intratumoural accumulation of maturated dendritic cells, reducing the growth of murine lymphoma developed with EL‐4 cells (Martner et al ., ).…”

Pharmacological Modulation of Proton Channel Hv1 in Cancer Therapy: Future Perspectives

“…Remarkably, EL-4 tumor-bearing mice treated in vivo with histamine showed a higher accumulation of intratumoral dendritic cells that associated with a significant reduction of tumor growth. These consequences of histamine treatment were not observed in NOX-deficient mice, indicating that the effects of histamine were mediated by the NOX2 regulation (Martner et al, 2015).…”

“…More recently, Martner et al (2015) provided evidence that the NOX2 inhibitor histamine promoted the maturation of human dendritic cells from monocytes, and this is characterized by an increased expression of human leukocyte antigen-antigen D related and costimulatory molecules, along with an enhanced ability to stimulate T helper cells with Th0 phenotype. Remarkably, EL-4 tumor-bearing mice treated in vivo with histamine showed a higher accumulation of intratumoral dendritic cells that associated with a significant reduction of tumor growth.…”