Histamine: a novel approach to cancer immunotherapy.
The functions of intratumoral lymphocytes in many human malignant tumors are inhibited by reactive oxygen species (ROS), generated by adjacent monocytes/macrophages (MO). In vitro data suggest that immunotherapeutic cytokines such as interleukin-2 (IL-2) or interferon-alpha (IFN-alpha) only weakly activate T cells or natural killer (NK) cells in a reconstituted environment of oxidative stress and that inhibitors of the formation of ROS or scavengers of ROS synergize with IL-2 and IFN-alpha to activate T cells and NK cells. 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 synergizes 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 adjunct to immunotherapy with IL-2 and/or IFN-alpha is currently evaluated in clinical trials in metastatic malignant melanoma and acute myelogenous leukemia.
Hellstrand
K
K
Department of Virology, University of Göteborg, Sweden. kristoffer.hellstrand@microbio.gu.se
Brune
M
M
Naredi
P
P
Mellqvist
U H
UH
Hansson
M
M
Gehlsen
K R
KR
Hermodsson
S
S
D004359:Drug Therapy, Combination; D006632:Histamine / Q000627:therapeutic use*; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000627:therapeutic use*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D009369:Neoplasms / Q000628:therapy*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D011968:Receptors, Histamine / Q000502:physiology
D007376:Interleukin-2; D017382:Reactive Oxygen Species; D011968:Receptors, Histamine; D006632:Histamine; D007371:Interferon-gamma