Lymphocyte number still remains one of the most important immune parameters predicting the prognosis of advanced
cancer patients.
IL-2 and
IL-12 are the main antitumor
cytokines in humans, and their effect is modulated by the neuroendocrine system, mainly by the pineal gland through the circadian release of
melatonin (MLT) and perhaps that of other
indole hormones, such as
5-methoxytryptamine (5-MTT), and
5-methoxytryptophol (5-MTP). MLT has been proven to exert important antitumor immunomodulating effects, whereas the possible immunomodulatory properties of the other pineal
indoles are still controversial. In an attempt to better define the pineal neuroendocrine regulation of the anticancer
cytokine network, we have evaluated in metastatic solid-
tumor patients the effects on lymphocyte number induced by different neuroimmune regimens, consisting of MLT alone (20 mg/day orally in the evening), subcutaneous (s.c.) low-dose
IL-2 alone (3 MIU/day in the evening for 6 days/week), s.c. low-dose
IL-12 alone (0.5 mcg/kg once/week in the morning),
IL-12 plus MLT,
IL-2 plus MLT, and
IL-2 plus MLT plus 5-MTT (10 mg/day orally in the afternoon) plus 5-MTP (5 mg/day orally at noon). The results showed the following evidence: (1) MLT alone is unable to induce
lymphocytosis; (2) MLT significantly enhances IL-2-induced
lymphocytosis; (3)
IL-12 alone determines
lymphocytopenia, which can be reversed by MLT; (4)
IL-2 plus
IL-12 induces a very pronounced
lymphocytosis, which can be further amplified by MLT; (5) a total pineal endocrine replacement
therapy with MLT, 5-MTT, and 5-MTP further increases IL-2-induced
lymphocytosis with respect to MLT plus
IL-2 alone. Therefore, this study confirms that IL-2- and IL-12-dependent anticancer immunity is under a pineal modulation.