We recently reported that stress can prevent immuno-stimulatory agents (ISAs) (e.g., IL-12) from activating cell-mediated immunity (CMI) and from controlling cancer metastasis in animal models. This phenomenon may partly account for the lesser success of ISA use in cancer patients relative to animal studies, as unlike animals in preclinical studies, cancer patients often experience marked anxiety and stress while treated with ISAs. This problem may be especially critical during the short peri-operative period in cancer patients, when immune stimulation could potentially promote patients'ability to control residual tumor progression after tumor removal, but deleterious psychological and physiological stress responses are heightened. Additionally, even if successful immune stimulation is achieved pre-operatively, surgery often causes profound suppression of CMI, rendering pre-operative immune stimulation ineffective. To overcome these obstacles, in the proposed study we aim to: (i) elucidate neuroendocrine, immune, [and tumor-related cellular and molecular] mechanisms via which various stressors dampen the beneficial effects of different ISAs;(ii) assess the biological significance of this phenomenon, using several models of cancer metastasis that bear clinical relevance;(iii) devise and test prophylactic approaches of potential clinical applicability to circumvent these deleterious effects of stress on immune stimulation;and (iv) in the context of primary tumor excision, compose integrated regimens that enable both successful peri-operative immune stimulation under stressful conditions, as well as the blockade of the deleterious effects of surgery on immunity and on resistance to tumor metastasis. To achieve these goals we will use psychological and physiological stress paradigms and study the efficacy of [two] different clinically approved ISAs, which are novel synthetic compounds (CpG-C, &GLA) that are under clinical investigation and can be used with minimal adverse effects during the peri-operative period. The prevention of the deleterious effects of surgery [itself] wil build on our recently-devised pharmacological intervention based on a COX2 inhibition and a ?-adrenergic blockade, which is now approved for clinical testing. Immune indices to be studied will include recently- recognized immune mechanisms that are critical for controlling tumor progression, including marginating- pulmonary and marginating-hepatic immunocytes, killer dendritic cells, memory-like NK cells, and several molecular determinants of anti-metastatic CMI. Cancer progression will be studied employing models of breast, colon, lung, and skin cancer metastasis in mice and rats. [Excised primary tumors will be analyzed], and metastatic development will be repeatedly monitored by bioluminescence-based imaging. The clinically important outcome of survival rates will also be assessed in orthotopic models of spontaneous metastasis. The proposed studies will strive both to elucidate basic mechanisms of interaction between stress and immune stimulation at the systemic and molecular levels, and to translate these insights into clinically feasible therapeutic approaches that can be used in cancer patients undergoing curative cancer resection.
We recently found that immune stimulation can be severely jeopardized by stress responses. In cancer patients the ample psychological, physiological, and surgery-induced stress responses can thus constitute obstacles to effective immune stimulation around the critical time of surgery, as our preliminary studies indeed suggest. In the proposed project we aim at elucidating underlying mechanisms of such deleterious effects of stress and surgery, with the goal of devising prophylactic measures that will enable an effective use of immune stimulation in cancer patients during the important period of surgery for the removal of the primary tumor.
|Levi, B; Matzner, P; Goldfarb, Y et al. (2016) Stress impairs the efficacy of immune stimulation by CpG-C: Potential neuroendocrine mediating mechanisms and significance to tumor metastasis and the perioperative period. Brain Behav Immun 56:209-20|
|Shaashua, Lee; Sorski, Liat; Melamed, Rivka et al. (2016) Selective Harvesting of Marginating-pulmonary Leukocytes. J Vis Exp :|
|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|
|Gotlieb, Neta; Rosenne, Ella; Matzner, Pini et al. (2015) The misleading nature of in vitro and ex vivo findings in studying the impact of stress hormones on NK cell cytotoxicity. Brain Behav Immun 45:277-86|
|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|
|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|