Histamine in cancer immunotherapy: a preclinical background

Semin Oncol. 2002 Jun;29(3 Suppl 7):35-40. doi: 10.1053/sonc.2002.33081.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adjuvants, Immunologic / therapeutic use*
  • Animals
  • Antineoplastic Agents / therapeutic use
  • Cytotoxicity, Immunologic* / physiology
  • Histamine / therapeutic use*
  • Humans
  • Immunologic Factors / therapeutic use
  • Immunotherapy, Active*
  • Immunotherapy, Adoptive*
  • Interferon-alpha / therapeutic use
  • Interleukin-2 / therapeutic use
  • Killer Cells, Natural / physiology
  • Melanoma / immunology
  • Melanoma / therapy
  • Monocytes / physiology
  • Reactive Oxygen Species
  • T-Lymphocyte Subsets / physiology


  • Adjuvants, Immunologic
  • Antineoplastic Agents
  • Immunologic Factors
  • Interferon-alpha
  • Interleukin-2
  • Reactive Oxygen Species
  • Histamine