Alleviating oxidative stress in cancer immunotherapy: a role for histamine?

Interleukin-2 is a remarkable activator of lymphocytes with anti-neoplastic properties such as T-cells or natural killer cells, but tumor regression o nly rarely occurs in interleukin-2-treated cancer patients. In this review, we focus on interactions between monocytes/macrophages and T-cells/natural killer-cells, and in particular the role of such interactions tor the outc ome of cancer immunotherapy with interleukin-2. We propose that interleukin -2 therapy should be supplemented with compounds that alleviate toxicity in flicted by monocyte/macrophage-derived reactive oxygen metabolites within a nd around tumors. The hypothesis is founded on data demonstrating that (i) functions of intratumoral lymphocytes in many human malignant tumors are in hibited by reactive oxygen metabolites, generated by neighboring monocytes/ macrophages, (ii) interleukin-2 only weakly activates T-cells or natural ki ller cells in an environment of oxidative stress, and (iii) inhibitors of t he formation of reactive oxygen metabolites or scavengers of reactive oxyge n metabolites synergize with interleukin-2 to activate these lymphocyte sub sets. We also review the preclinical background to the use of histamine dih ydrochloride, an inhibitor of reactive oxygen metabolite formation in monoc ytes/macrophages, as a supplement to cancer immunotherapy with interleukin- 2.