Inducing a Mode of NK-Resistance to Suppression by Stress and Surgery: a Potential Approach Based on Low Dose of Poly I-C to Reduce Postoperative Cancer Metastasis

摘要

Perioperative suppression of NK activity has been suggested to compromise host resistance to tumor progression. Here we sought to develop a clinically applicable pre-operative regimen to prevent immunosuppression and promotion of metastasis by stress or surgery. The synthetic ds-RNA, poly I-C, was used in vivo in F344 rats, based on its alleged in vitro ability to protect immunocytes from suppression by cAMP elevating agents. Different regimens of poly I-C were studied in controls and in rats subjected to a pharmacological stressor, swim stress, or surgical stress. Resistance to lung experimental metastasis of the syngeneic non-immunogenic MADB106 mammary adenocarcinoma was assessed. Numbers of circulating and marginating-pulmonary NK cells and their cytotoxicity against the MADB106 and YAC-1 target lines were also studied. Our findings established a regimen of repeated low-dose poly I-C administration with minimal side effects (0.2 mg/kg i.p. 5, 3, & 1 day before tumor inoculation). This regimen, while hardly affecting resistance levels in non-stressed animals, prevented all stressors from promoting metastases. These beneficial effects occurred in the presence of a primary tumor and in both sexes. Poly I-C increased the numbers of NK cells, and, on a per NK cell basis, while not increasing cytotoxicity, profoundly protected marginating-pulmonary NK cells from suppression by surgery. This study suggests a non-toxic clinically-translatable prophylactic use of poly I-C to target the critical perioperative period. By increasing the number of marginating-pulmonary NK cells, and by transforming them into a mode of resistance to immunosuppression, this approach may reduce postoperative metastasis in cancer patients.