Synergism between immunostimulation and prevention of surgery-induced immune suppression: an approach to reduce post-operative tumor progression.
BACKGROUND
A unique opportunity to eradicate cancer is presented immediately after the excision of the primary tumor, but surgical procedures often induce the release of immunosuppressing factors that render cell mediated immunity ineffective. Here we tested the hypothesis that integration of peri-operative immunostimulation and blockade of immunosuppression could synergistically improve post-operative anti-metastatic immunity and long-term survival.


METHODS
Two syngeneic tumor models in F344 rats were employed, studying post-operative tumor progression. In the first model, survival following laparotomy and CRNK-16 leukemia was studied. Rats were peri-operatively treated with the immuno-stimulant poly I-C (5x0.2 mg/kg/inj), with catecholamine- and prostaglandin-blockers (shown to prevent post-operative immunosuppression: 4.5 mg/kg nadolol, 4 mg/kg indomethacin), with both interventions, or with neither. Long-term survival was assessed thereafter. The second model used the MADB106 mammary adenocarcinoma, assessing its lung tumor retention (LTR) following i.v. inoculation, as well as host marginating-pulmonary NK numbers and activity against this tumor. IL-12 was employed for immunostimulation (4x1.5 microg/kg/inj), with and without the above blockers.


RESULTS
Post-operative CRNK-16 survival rates were significantly improved only by the integrated approach of immune stimulation and endocrine blockers. Post-operative MADB106 LTR was additively reduced by the two interventions. Importantly, while IL-12 increased pulmonary NK cytotoxicity against MADB106, surgery markedly suppressed this cytotoxicity in both IL-12 and vehicle treated animals. The blockers prevented this suppression per lung and per single NK cell.


CONCLUSIONS
Immunostimulation could be rendered ineffective post-operatively due to immunosuppression; therefore integrating endocrine-blocker therapies into the realm of peri-operative immunotherapy could optimize immune control over residual disease, potentially improving clinical outcomes.
Avraham
Roi
R
Department of Psychology, Tel Aviv University, Tel Aviv, Israel.
Benish
Marganit
M
Inbar
Shelly
S
Bartal
Inbal
I
Rosenne
Ella
E
Ben-Eliyahu
Shamgar
S
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002395:Catecholamines / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D018450:Disease Progression; D005434:Flow Cytometry; D006727:Hormone Antagonists / Q000494:pharmacology; D007108:Immune Tolerance / Q000502:physiology*; D007213:Indomethacin / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D007694:Killer Cells, Natural; D007813:Laparotomy; D008175:Lung Neoplasms / Q000473:pathology; D009248:Nadolol / Q000494:pharmacology; D009374:Neoplasms, Experimental / Q000473:pathology* / Q000601:surgery*; D011070:Poly I-C / Q000494:pharmacology; D011183:Postoperative Complications / Q000276:immunology* / Q000473:pathology*; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013534:Survival
D000276:Adjuvants, Immunologic; D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D016861:Cyclooxygenase Inhibitors; D006727:Hormone Antagonists; D011448:Prostaglandin Antagonists; D018664:Interleukin-12; D009248:Nadolol; D011070:Poly I-C; D007213:Indomethacin