Amelioration of operation-induced suppression of marginating pulmonary NK activity using poly IC: a potential approach to reduce postoperative metastasis.
OBJECTIVE
Pulmonary metastasis is a major cause of death in cases of operable cancer, and evidence suggests that postoperative immunosuppression contributes to this complication. In this study, we aimed to circumvent this risk and identify immunocytes critical in preventing pulmonary metastases.


METHODS
F344 rats were treated with either vehicle or repeated low doses of poly I-C (0.2 mg/kg i.p., days 5, 3, and 1 preoperatively), a Th1-cytokine-inducing agent, then subjected or not to laparotomy. Using a non-immunogenic syngeneic mammary adenocarcinoma line (MADB106) we studied: (a) NK cytotoxicity (NKC) in marginating-pulmonary (MP) and in circulating leukocytes; (b) resistance to experimental lung metastasis; and (c) in vitro susceptibility of NKC to corticosterone and prostaglandin-E(2), substances thought to mediate postoperative immunosuppression.


RESULTS
MP but not circulating leukocytes showed significant NKC against MADB106 cells. Surgery suppressed this MP-NKC per NK cell and promoted MADB106 metastasis, and poly I-C treatment completely abolished both effects. Poly I-C quadrupled the numbers of MP-NK cells without causing apparent side effects, and protected MP-NKC from in vitro suppression by corticosterone and prostaglandin-E(2).


CONCLUSIONS
MP-NK cells are unique in their ability to kill this apparently immunoresistant tumor. Low doses of synthetic ds-RNA (poly I-C), and potentially Th1 cytokines, can expand this MP-NK population and protect it from immunosuppression. The novelty of such a prophylactic approach is targeting the immediate postoperative period, which is characterized by high vulnerability to residual disease, and protecting critical anti-metastatic immunity against postoperative suppression. Testing such a potentially innocuous intervention in oncology patients preparing for surgery may reduce metastatic recurrence.
Shakhar
Guy
G
Department of Immunology, Weizmann Institute of Science, Rehovot, 76100, Israel.
Abudarham
Naphtali
N
Melamed
Rivka
R
Schwartz
Yossi
Y
Rosenne
Ella
E
Ben-Eliyahu
Shamgar
S
D000230:Adenocarcinoma; D000818:Animals; D045744:Cell Line, Tumor; D003345:Corticosterone / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007369:Interferon Inducers / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D007813:Laparotomy / Q000009:adverse effects; D008168:Lung / Q000166:cytology; D008175:Lung Neoplasms / Q000276:immunology* / Q000517:prevention & control / Q000556:secondary; D008297:Male; D008325:Mammary Neoplasms, Experimental; D009362:Neoplasm Metastasis; D011070:Poly I-C / Q000494:pharmacology*; D011183:Postoperative Complications; D051381:Rats; D011916:Rats, Inbred F344; D019139:Tumor Escape / Q000187:drug effects / Q000276:immunology*
D007166:Immunosuppressive Agents; D007369:Interferon Inducers; D015232:Dinoprostone; D011070:Poly I-C; D003345:Corticosterone