Do stress responses promote leukemia progression? An animal study suggesting a role for epinephrine and prostaglandin-E2 through reduced NK activity.

In leukemia patients, stress and anxiety were suggested to predict poorer prognosis. Oncological patients experience ample physiological and psychological stress, potentially leading to increased secretion of stress factors, including epinephrine, corticosteroids, and prostaglandins. Here we tested whether environmental stress and these stress factors impact survival of leukemia-challenged rats, and studied mediating mechanisms. F344 rats were administered with a miniscule dose of 60 CRNK-16 leukemia cells, and were subjected to intermittent forced swim stress or to administration of physiologically relevant doses of epinephrine, prostaglandin-E(2) or corticosterone. Stress and each stress factor, and/or their combinations, doubled mortality rates when acutely applied simultaneously with, or two or six days after tumor challenge. Acute administration of the ß-adrenergic blocker nadolol diminished the effects of environmental stress, without affecting baseline survival rates. Prolonged ß-adrenergic blockade or COX inhibition (using etodolac) also increased baseline survival rates, possibly by blocking tumor-related or normal levels of catecholamines and prostaglandins. Searching for mediating mechanisms, we found that each of the stress factors transiently suppressed NK activity against CRNK-16 and YAC-1 lines on a per NK basis. In contrast, the direct effects of stress factors on CRNK-16 proliferation, vitality, and VEGF secretion could not explain or even contradicted the in vivo survival findings. Overall, it seems that environmental stress, epinephrine, and prostaglandins promote leukemia progression in rats, potentially through suppressing cell mediated immunity. Thus, patients with hematological malignancies, which often exhibit diminished NK activity, may benefit from extended ß-blockade and COX inhibition.

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.

Autologous control of a highly malignant syngeneic CRNK-16 leukemia in the rat: a role for NK cells.

It is unclear whether autologous immunity could be recruited to restrict the progression of leukemia. Patients harboring leukemia commonly display suppressed cell mediated immunity, which may contribute to their inability to control the disease. Immune response against leukemia is evident in allogeneic HLA-mismatched bone marrow transplantation, implicating the involvement of NK cells. This graft-versus-leukemia (GVL) activity suggests that, if not suppressed, an autologous NK cell response could potentially control acute leukemia that had down-regulated HLA expression. In the current study we assessed the role of non-suppressed autologous NK cells in controlling a syngeneic highly malignant leukemia, the CRNK-16 line, that constitute a major cause of natural death in aged F344 rats. A minuscule dose of 60 CRNK-16 leukemia cells per rat was sufficient to induce 50% mortality rates, and animals that survived this challenge did not show improved survival upon a second challenge. The CRNK-16 line was found to exhibit low levels of MHC-I, and selective in vivo depletion of NK cells nullified in vitro NK activity against the CRNK-16 line and reduced survival rates from this leukemia. In vivo activation of NK cells, employing low doses of poly I-C or IL-12, increased in vitro NK activity against the leukemia and dramatically improved survival rates when treatment was initiated before, but not after leukemia inoculation. These results indicate the ability of competent autologous NK cells to restrict highly malignant non-immunogenic leukemia. Thereby, this model presents an opportunity to study specific in vivo NK-leukemia interactions.