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.
Perioperative suppression of NK activity has been suggested to compromise host resistance to tumor progression. Here, we sought to develop a clinically applicable preoperative 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 (0.2mg/kg i.p. 5, 3, and 1day 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.
Rosenne
Ella
E
Neuroimmunology Research Unit, Department of Psychology, Tel Aviv University, Tel Aviv 69978, Israel.
Shakhar
Guy
G
Melamed
Rivka
R
Schwartz
Yossi
Y
Erdreich-Epstein
Anat
A
Ben-Eliyahu
Shamgar
S
D000230:Adenocarcinoma / Q000556:secondary* / Q000601:surgery; D000704:Analysis of Variance; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology* / Q000601:surgery; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D007108:Immune Tolerance; D007369:Interferon Inducers / Q000008:administration & dosage* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary* / Q000601:surgery; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008223:Lymphoma / Q000473:pathology; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D011070:Poly I-C / Q000008:administration & dosage* / Q000494:pharmacology; D011183:Postoperative Complications / Q000517:prevention & control; D051381:Rats; D011916:Rats, Inbred F344; D013312:Stress, Physiological / Q000150:complications / Q000276:immunology
D007369:Interferon Inducers; D011070:Poly I-C