Abstract
Despite the well-known importance of lymphocytes in tumor cell destruction and the evidence that lymphocytopenia is associated with a poor prognosis and lower survival in almost all tumor histotypes, lymphocyte count is not generally taken into consideration by the oncologists and no specific protocol has been proposed to treat cancer-related lymphocytopenia because of its negative impact on the clinical course of the neoplastic disease. Obviously, the most effective agents to stimulate the proliferation of lymphocytes would have to be their major growth factor, consisting of IL-2, whose in vivo biological activity may be further amplified by an association with some neuro-immunomodulating agents, such as the pineal hormone melatonin (MLT). This study was performed to evaluate the effects of subcutaneous (SC) low-dose IL-2 plus high-dose MLT in a group of metastatic cancer patients with persistent lymphocytopenia, who failed to respond to the standard anticancer therapies. The study included 14 patients who received MLT orally at 100 mg/day in the evening every day without interruption plus IL-2 SC at 1.8 MIU/day for five days a week for two consecutive weeks, corresponding to one complete cycle. A second cycle was repeated after a rest period of two weeks. A normalization of lymphocyte count was achieved in 9/14 (64%) patients, 4 of them (29%) just after the first week of therapy. Because of the association between cancer-related lymphocytopenia and lower survival and the fundament role of lymphocyte in mediating cancer cell destruction, the correction of advanced cancer-related lymphocytopenia by a short-term SC low-dose IL-2 therapy could improve the clinical course of cancer patients, including those suitable for the only palliative treatment.
Highlights
The failure of the antitumor immunity in advanced cancer patients does not depend only on a deficiency of T lymphocyte system, including T helper (Th) (CD4+) and cytotoxic T lymphocytes (CD8+) [1, 2, 3], and on a concomitant enhanced activation of the macrophage system [4, 5, 6]
This evidence would suggest that the effect of IL-2 on lymphocyte number may depend on its concomitant effect on monocyte count, which has been proven to reflect the activity of the macrophage system and macrophage-tumor infiltration, which has appeared to be associated with a poor prognosis in cancer patients [4, 5, 6, 7]
Because of its ability to stimulate lymphocyte proliferation, this study would suggest that IL-2 may be used to indirectly influencing tumor progression by correcting cancer-related lymphocytopenia, since the evidence of low lymphocyte count has been proven to predict a poor prognosis in advanced cancer patients [15]
Summary
The failure of the antitumor immunity in advanced cancer patients does not depend only on a deficiency of T lymphocyte system, including T helper (Th) (CD4+) and cytotoxic T lymphocytes (CD8+) [1, 2, 3], and on a concomitant enhanced activation of the macrophage system [4, 5, 6]. In addition to its inhibitory effects on macrophage-mediated inflammatory response, MLT has been proven to directly stimulate Th cell proliferation and IL-2 secretion by acting on specific MLT receptors expressed by lymphocytes themselves. Lymphocyte count could be enhanced through an immune way by the administration of cytokines such as IL-2 and, namely, IL-2 itself, or alternatively through a neuroimmune approach with molecules provided by neuro-immunomodulating
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