Grant Number:	5R01CA172138-05 Interpret this number
Primary Investigator:	Ben-Eliyahu, Shamgar
Organization:	Tel Aviv University
Project Title:	Stress Undermines Immune Stimulation: Mechanisms & Biological Significance
Fiscal Year:	2017

DESCRIPTION (provided by applicant): 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.




Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome.
Authors: Shaashua L. , Eckerling A. , Israeli B. , Yanovich G. , Rosenne E. , Fichman-Horn S. , Ben Zvi I. , Sorski L. , Haldar R. , Satchi-Fainaro R. , et al. .
Source: Bmc Biology, 2020-11-06 00:00:00.0; 18(1), p. 163.
EPub date: 2020-11-06 00:00:00.0.
PMID: 33158447
Related Citations

Tumor Excision as a Metastatic Russian Roulette: Perioperative Interventions to Improve Long-Term Survival of Cancer Patients.
Authors: Ben-Eliyahu S. .
Source: Trends In Cancer, 2020 11; 6(11), p. 951-959.
EPub date: 2020-07-10 00:00:00.0.
PMID: 32654993
Related Citations

Prevention of liver metastases through perioperative acute CpG-C immune stimulation.
Authors: Sorski L. , Melamed R. , Levi B. , Matzner P. , Lavon H. , Rosenne E. , Shaashua L. , Ricon I. , Sandbank E. , Benbenishty A. , et al. .
Source: Cancer Immunology, Immunotherapy : Cii, 2020-05-13 00:00:00.0; , .
EPub date: 2020-05-13 00:00:00.0.
PMID: 32405793
Related Citations

Perioperative biobehavioral interventions to prevent cancer recurrence through combined inhibition of β-adrenergic and cyclooxygenase 2 signaling.
Authors: Ricon I. , Hanalis-Miller T. , Haldar R. , Jacoby R. , Ben-Eliyahu S. .
Source: Cancer, 2018-10-06 00:00:00.0; , .
EPub date: 2018-10-06 00:00:00.0.
PMID: 30291805
Related Citations

Regeneration of Functional Adrenal Tissue Following Bilateral Adrenalectomy.
Authors: Gotlieb N. , Albaz E. , Shaashua L. , Sorski L. , Matzner P. , Rosenne E. , Amram B. , Benbenishty A. , Golomb E. , Ben-Eliyahu S. .
Source: Endocrinology, 2018-01-01 00:00:00.0; 159(1), p. 248-259.
PMID: 29059290
Related Citations

Maintaining Unperturbed Cerebral Blood Flow Is Key In The Study Of Brain Metastasis And Its Interactions With Stress And Inflammatory Responses
Authors: Amit B. , Niva S.A. , Lee S. , Rivka M. , Shamgar B.E. , Pablo B. .
Source: Brain, Behavior, And Immunity, 2017 May; 62, p. 265-276.
PMID: 28219803
Related Citations

Reducing Liver Metastases Of Colon Cancer In The Context Of Extensive And Minor Surgeries Through ¿-adrenoceptors Blockade And Cox2 Inhibition
Authors: Sorski L. , Melamed R. , Matzner P. , Lavon H. , Shaashua L. , Rosenne E. , Ben-Eliyahu S. .
Source: Brain, Behavior, And Immunity, 2016 Nov; 58, p. 91-98.
PMID: 27235931
Related Citations

Stress impairs the efficacy of immune stimulation by CpG-C: Potential neuroendocrine mediating mechanisms and significance to tumor metastasis and the perioperative period.
Authors: Levi B. , Matzner P. , Goldfarb Y. , Sorski L. , Shaashua L. , Melamed R. , Rosenne E. , Page G.G. , Ben-Eliyahu S. .
Source: Brain, Behavior, And Immunity, 2016 Aug; 56, p. 209-20.
PMID: 26944000
Related Citations

Selective Harvesting Of Marginating-hepatic Leukocytes
Authors: Sorski L. , Shaashua L. , Melamed R. , Matzner P. , Ben-Eliyahu S. .
Source: Journal Of Visualized Experiments : Jove, 2016-07-21 00:00:00.0; (113), .
PMID: 27500423
Related Citations

Perioperative treatment with the new synthetic TLR-4 agonist GLA-SE reduces cancer metastasis without adverse effects.
Authors: Matzner P. , Sorski L. , Shaashua L. , Elbaz E. , Lavon H. , Melamed R. , Rosenne E. , Gotlieb N. , Benbenishty A. , Reed S.G. , et al. .
Source: International Journal Of Cancer, 2016-04-01 00:00:00.0; 138(7), p. 1754-64.
EPub date: 2016-04-01 00:00:00.0.
PMID: 26453448
Related Citations

Selective Harvesting of Marginating-pulmonary Leukocytes.
Authors: Shaashua L. , Sorski L. , Melamed R. , Ben-Eliyahu S. .
Source: Journal Of Visualized Experiments : Jove, 2016-03-11 00:00:00.0; (109), .
EPub date: 2016-03-11 00:00:00.0.
PMID: 27023665
Related Citations

Exploiting The Critical Perioperative Period To Improve Long-term Cancer Outcomes
Authors: Horowitz M. , Neeman E. , Sharon E. , Ben-Eliyahu S. .
Source: Nature Reviews. Clinical Oncology, 2015 Apr; 12(4), p. 213-26.
PMID: 25601442
Related Citations

The misleading nature of in vitro and ex vivo findings in studying the impact of stress hormones on NK cell cytotoxicity.
Authors: Gotlieb N. , Rosenne E. , Matzner P. , Shaashua L. , Sorski L. , Ben-Eliyahu S. .
Source: Brain, Behavior, And Immunity, 2015 Mar; 45, p. 277-86.
PMID: 25546569
Related Citations

Impact of surgical extent and sex on the hepatic metastasis of colon cancer.
Authors: Sorski L. , Levi B. , Shaashua L. , Neeman E. , Benish M. , Matzner P. , Hoffman A. , Ben-Eliyahu S. .
Source: Surgery Today, 2014 Oct; 44(10), p. 1925-34.
PMID: 24190423
Related Citations

Plasma IL-12 levels are suppressed in vivo by stress and surgery through endogenous release of glucocorticoids and prostaglandins but not catecholamines or opioids.
Authors: Shaashua L. , Rosenne E. , Neeman E. , Sorski L. , Sominsky L. , Matzner P. , Page G.G. , Ben-Eliyahu S. .
Source: Psychoneuroendocrinology, 2014 Apr; 42, p. 11-23.
PMID: 24636497
Related Citations

In vivo suppression of NK cell cytotoxicity by stress and surgery: glucocorticoids have a minor role compared to catecholamines and prostaglandins.
Authors: Rosenne E. , Sorski L. , Shaashua L. , Neeman E. , Matzner P. , Levi B. , Ben-Eliyahu S. .
Source: Brain, Behavior, And Immunity, 2014 Mar; 37, p. 207-19.
PMID: 24333572
Related Citations

The marginating-pulmonary immune compartment in mice exhibits increased NK cytotoxicity and unique cellular characteristics.
Authors: Benish M. , Melamed R. , Rosenne E. , Neeman E. , Sorski L. , Levi B. , Shaashua L. , Matzner P. , Ben-Eliyahu S. .
Source: Immunologic Research, 2014 Jan; 58(1), p. 28-39.
PMID: 24132552
Related Citations

Surgery and stress promote cancer metastasis: new outlooks on perioperative mediating mechanisms and immune involvement.
Authors: Neeman E. , Ben-Eliyahu S. .
Source: Brain, Behavior, And Immunity, 2013 Mar; 30 Suppl, p. S32-40.
PMID: 22504092
Related Citations

PGE2 suppresses NK activity in vivo directly and through adrenal hormones: effects that cannot be reflected by ex vivo assessment of NK cytotoxicity.
Authors: Meron G. , Tishler Y. , Shaashua L. , Rosenne E. , Levi B. , Melamed R. , Gotlieb N. , Matzner P. , Sorski L. , Ben-Eliyahu S. .
Source: Brain, Behavior, And Immunity, 2013 Feb; 28, p. 128-38.
PMID: 23153554
Related Citations