Histamine: A novel approach to cancer immunotherapy

The functions of intratumoral lymphocytes in many human malignant tumors ar e inhibited by reactive oxygen species (ROS), generated by adjacent monocyt es/macrophages (MO). In vitro data suggest that immunotherapeutic cytokines such as interleukin-2 (IL-2) or interferon-alpha (IFN-alpha) only weakly a ctivate T cells or natural killer (NK) cells in a reconstituted environment of oxidative stress and that inhibitors of the formation of ROS or scaveng ers of ROS synergize with IL-2 and IFN-alpha to activate T cells and NK cel ls. In this review, we focus on the immunoenhancing properties of histamine , a biogenic amine. Histamine inhibits ROS formation in MO via H2-receptors ; thereby, histamine protects NK cells from MO-mediated inhibition and syne rgizes with IL-2 and IFN-alpha to induce killing of NK cell-sensitive human tumor cells in vitro. Histamine also optimizes cytokine-induced activation of several subsets of T cells by affording protection against MO-inflicted oxidative inhibition. The putative clinical benefit of histamine as an adj unct to immunotherapy with IL-2 and/or IFN-alpha is currently evaluated in clinical trials in metastatic malignant melanoma and acute myelogenous leuk emia.