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CpG-C Oligodeoxynucleotides Limit the Deleterious Effects of β-adrenoceptor Stimulation on NK Cytotoxicity and Metastatic Dissemination

Suppression of natural killer (NK) cell activity is common after stress, has been reported to predict malignant recurrence in cancer patients, and was shown to underlie metastatic dissemination in animal models. We have previously reported that catecholamines play a major role in NK cell suppression, particularly in the context of physiologic stress and surgery. In the current study using Fisher 344 rats, we examined the prophylactic use of different regimens of type-C CpG oligodeoxynucleotides (CpG-C ODN) on NK activity and metastatic dissemination in the context of pharmacologic stress (using metaproterenol for β-adrenoceptor stimulation). Our results indicated that the beneficial effects of CpG-C ODN were more profound under pharmacologic stress than under baseline conditions. A bolus of CpG-C ODN (330 μg/kg, intraperitoneally) 24 hours before metaproterenol-challenge was most effective at reducing lung tumor retention of an experimental syngeneic mammary adenocarcinoma (MADB106), although having no observable side effects. Depletion of NK cells revealed their key role in improving baseline levels of resistance to metastatic dissemination after CpG-C ODN administration. When NK cell cytotoxicity was assessed in the circulation and the marginating-pulmonary immune compartments, we found that CpG-C ODN protected individual NK cells from metaproterenol-induced suppression in both compartments. Moreover, in the critical marginating-pulmonary compartment, CpG-C ODN also elevated baseline cytotoxicity per NK cell against MADB106 tumor cells, and increased NK cell numbers in nonstressed rats. Overall, prophylactic CpG-C ODN treatment can improve immunocompetence and potentially reduce metastatic dissemination, especially in clinical settings characterized by enhanced sympathetic stress responses.