Stress impairs the efficacy of immune stimulation by CpG-C: Potential neuroendocrine mediating mechanisms and significance to tumor metastasis and the perioperative period

Abstract

We recently reported that immune stimulation can be compromised if animals are simultaneously subjected to stressful conditions. To test the generalizability of these findings, and to elucidate neuroendocrine mediating mechanisms, we herein employed CpG-C, a novel TLR-9 immune-stimulating agent. Animals were subjected to ongoing stress (20-hrs of wet cage exposure) during CpG-C treatment, and antagonists to glucocorticoids, β-adrenoceptor, COX2, or opioids were employed (RU486, nadolol, etodolac, naltrexone). In F344 rats, marginating-pulmonary NK cell numbers and cytotoxicity were studied, and the NK-sensitive MADB106 experimental metastasis model was used. In Balb/C mice, experimental hepatic metastases of the CT-26 colon tumor were studied; and in C57BL/6J mice, survival rates following excision of B16 melanoma was assessed – both mouse tumor models involved surgical stress. The findings indicated that simultaneous blockade of glucocorticoid and β-adrenergic receptors improved CpG-C efficacy against MADB106 metastasis. In mice bearing B16 melanoma, long-term survival rate was improved by CpG-C only when employed simultaneously with blockers of glucocorticoids, catecholamines, and prostaglandins. Prolonged stress impaired CpG-C efficacy in potentiating NK activity, and in resisting MADB106 metastasis in both sexes, as also supported by in vitro studies. This latter effect was not blocked by any of the antagonists or by adrenalectomy. In the CT26 model, prolonged stress only partially reduced the efficacy of CpG-C. Overall, our findings indicate that ongoing behavioral stress and surgery can jeopardize immune-stimulatory interventions and abolish their beneficial metastasis-reducing impacts. These findings have implications for the clinical setting, which often involve psychological and physiological stress responses during immune-stimulation.

Surgical stress and cancer progression: the twisted tango

“…After βAR activation, inflammation-dependent mechanisms remodel tumor-associated lymphatic and blood vasculature, which in turn promote in vivo tumor cell dissemination [36]. Also, accumulating evidence has suggested that catecholamines have a stronger effect upon the immune system than glucocorticoids, and activation of the sympathetic nervous system suppresses natural killer cell response to tumor cells [47, 48].…”

Prophylactic TLR9 stimulation reduces brain metastasis through microglia activation

“…In various animal models, CpG-ODN treatment was shown to reduce mammary lung metastases by eliciting antitumor natural killer (NK) activity [9], and even results in rapid debulking of large tumors by macrophage stimulation [10]. Employed prophylactically, CpG-ODNs were shown to markedly improve resistance to experimental and spontaneous peripheral metastasis of mammary [11], colon [12], and melanoma [13] tumors.…”

“…However, to implement a prophylactic approach against brain metastases in a wider range of patients, a less toxic [18] treatment is required. TLR9 stimulation using CpG-ODNs is particularly well suited to meet this need, as it has negligible toxicity in humans [19–21], and has already promising preclinical outcomes in other organs [10–13]; therefore, it should also be considered a potential prophylactic approach against the establishment of brain metastases.…”

Neuroendocrine Regulation of Tumor-Associated Immune Cells

“…The adverse systemic effects of chronic stress on immune cells, such as immunosuppression, might impair the positive therapeutic responses and benefits seen by current immunotherapies, highlighting the need to address SNS activation on tumor biology. For instance, ongoing stress can impair the efficacy of therapies based on immune stimulation (24, 128).…”