THE ROLE OF CYCLIC-AMP AND OXYGEN INTERMEDIATES IN THE INHIBITION OF CELLULAR-IMMUNITY IN CANCER

Cell-mediated immunity is often impaired in cancer. This may be partly due to increased amounts of prostaglandin E(2) (PCE(2)) and histamine in the blood of cancer patients, since PGE(2) and histamine possess i nhibitory effects on cellular immunity. These effects are mediated by cyclic AMP (cAMP), which is increased in leukocytes by PGE(2) through EP2 and by histamine through H2 receptors and also by epinephrine thro ugh beta 2-adrenergic receptors. Increased cAMP activates protein kina se A, which inhibits the formation of interleukin 2 (IL-2) in T cells. The formation of interferon gamma is concomitantly decreased, and cel lular immunity is attenuated. In monocyte/macrophages the formation of IL-1 beta, IL-12 and tumor necrosis factor alpha is decreased by cAMP or through the increased formation of IL-10, which is up-regulated by cAMP. This attenuates cellular immunity. In monocytes histamine may d ecrease the formation of oxygen intermediates, which can induce apopto sis of natural killer cells and thus inhibit immunity. The superoxide anion is a potent inducer of the cyclooxygenase-2 enzyme, which is up- regulated in colorectal cancer. Cyclooxygenase-2 catalyzes the formati on of PGE(2), e.g. in cancer cells. Thus the inhibition of cellular im munity in cancer may be at least partly mediated by cAMP and oxygen in termediates. This may offer new options for cancer immunotherapy.