Histamine in cancer immunotherapy: a preclinical background

Natural killer (NK) cells and T cells are the primary targets of interleukin-2 (IL-2) and other cytokines used in cancer immunotherapy. However, these tumoricidal lymphocytes are frequently dysfunctional or apoptotic when residing within melanomas and other solid cancers. This phenomenon--tumor-induced immunosuppression--is poorly understood and conceivably limits the efficiency of strategies aiming at activating lymphocyte-mediated antitumor immunity. Recent studies imply that reactive oxygen species (oxygen radicals), produced by tumor-infiltrating monocyte/macrophages, may contribute to the state of lymphocyte inhibition in neoplastic tissue. Histamine, acting via H2-type histamine receptors on monocyte/macrophages, suppresses the activity of a key enzyme in oxygen radical formation, the NADPH oxidase. By this mechanism, histamine protects NK cells and T cells against oxygen radical-induced dysfunction and apoptosis, and also maintains their activation by IL-2 and other lymphocyte activators. In this review, these properties of histamine are discussed in relation to the current use of histamine as an adjunct to IL-2 in metastatic melanoma and other malignant diseases.