Amelioration of operation-induced suppression of marginating pulmonary NK activity using poly IC: A potential approach to reduce postoperative metastasis

Guy Shakhar, Naphtali Abudarham, Rivka Melamed, Yossi Schwartz, Ella Rosenne, Shamgar Ben-Eliyahu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background and objectives: 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-E2, 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-E2. 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.

Original languageEnglish
Pages (from-to)841-852
Number of pages12
JournalAnnals of Surgical Oncology
Volume14
Issue number2
DOIs
StatePublished - Feb 2007

Funding

FundersFunder number
NIH/NCI
National Cancer InstituteR01CA073056
Israel Science Foundation

    Keywords

    • Lung
    • NK cells
    • Neuroimmunology
    • Rodents
    • Tumor Immunology

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