Immuno-stimulatory (IS) therapy in cancer patients is often more effective when combined with other interventions, and when limiting mechanisms are deactivated. Various stressors, neuroendocrine responses, and cytokines are known to modulate immune competence, and can thus modulate responses to IS agents and potentially dampen their therapeutic efficacy. Here we aim at studying potential interactions between psycho-neuro-immunological (PNI) processes and IS treatments, with the intention of unraveling underlying mechanisms, and potentiating immunotherapy. Our studies will revolve around three interrelated interactions: (1) Psychological stress before and during IS therapy is common in cancer patients, but is rarely simulated in animal models of immunotherapy. Stress responses often reduce TH1 and promote proinflammatory responses, potentially dampening beneficial impact of IS agents and worsening their side effects. (2) The host physiological response to IS agents includes perturbations in cytokines and stress hormones that can suppress cell mediated immunity (CMI) (see Preliminary Studies) and self-limit the efficacy of IS approaches. (3) At critical times, including the immediate post-operative period, successful IS approaches could be rendered ineffective by the clinically well-established suppression of CMI following major surgeries. Supplementing IS approaches with our recently developed PNI-based pharmacological interventions (see Preliminary Studies) can prevent such immune suppression, thus preserving the potential benefits of IS approaches. We propose to study and improve the efficacy of three immunostimulatory agents, IL-12, poly I-C, and CpG oligodeoxynucleotides (ODN), under ongoing social stress conditions and following surgery. Outcomes will include NK activation markers and cytotoxicity, cytokine levels and their induced production, and in vivo resistance to experimental and spontaneous metastasis in rodents (MADB106, B16, and 3LL tumors). Neuroendocrine and cytokine mediators of the deleterious effects of stress and of IS agents will be studied. Integrated protocols of immune stimulation and pharmacological blockade of deleterious stress and cytokine responses will be developed and used during stress, IS treatment, and surgery. The knowledge gained could reduce side effects and enhance the efficacy of immunotherapy before and after surgery, potentially increasing survival rates in cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA125456-05
Application #
8135379
Study Section
Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
Program Officer
Mc Donald, Paige A
Project Start
2007-09-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$185,986
Indirect Cost
Name
Tel Aviv University
Department
Type
DUNS #
600048417
City
Tel Aviv
State
Country
Israel
Zip Code
69978
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Matzner, Pini; Sorski, Liat; Shaashua, Lee et al. (2016) Perioperative treatment with the new synthetic TLR-4 agonist GLA-SE reduces cancer metastasis without adverse effects. Int J Cancer 138:1754-64
Sorski, Liat; Melamed, Rivka; Matzner, Pini et al. (2016) Reducing liver metastases of colon cancer in the context of extensive and minor surgeries through ?-adrenoceptors blockade and COX2 inhibition. Brain Behav Immun 58:91-98
Shaashua, Lee; Rosenne, Ella; Neeman, Elad et al. (2014) Plasma IL-12 levels are suppressed in vivo by stress and surgery through endogenous release of glucocorticoids and prostaglandins but not catecholamines or opioids. Psychoneuroendocrinology 42:11-23
Sorski, Liat; Levi, Ben; Shaashua, Lee et al. (2014) Impact of surgical extent and sex on the hepatic metastasis of colon cancer. Surg Today 44:1925-34
Rosenne, Ella; Sorski, Liat; Shaashua, Lee et al. (2014) In vivo suppression of NK cell cytotoxicity by stress and surgery: glucocorticoids have a minor role compared to catecholamines and prostaglandins. Brain Behav Immun 37:207-19
Benish, Marganit; Melamed, Rivka; Rosenne, Ella et al. (2014) The marginating-pulmonary immune compartment in mice exhibits increased NK cytotoxicity and unique cellular characteristics. Immunol Res 58:28-39
Meron, G; Tishler, Y; Shaashua, L et al. (2013) PGE2 suppresses NK activity in vivo directly and through adrenal hormones: effects that cannot be reflected by ex vivo assessment of NK cytotoxicity. Brain Behav Immun 28:128-38
Neeman, Elad; Ben-Eliyahu, Shamgar (2013) Surgery and stress promote cancer metastasis: new outlooks on perioperative mediating mechanisms and immune involvement. Brain Behav Immun 30 Suppl:S32-40
Goldfarb, Yael; Shapiro, Haim; Singer, Pierre et al. (2012) Fish oil attenuates surgery-induced immunosuppression, limits post-operative metastatic dissemination and increases long-term recurrence-free survival in rodents inoculated with cancer cells. Clin Nutr 31:396-404

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