Perioperative hypothermia and stress jeopardize antimetastatic immunity and TLR-9 immune activation: potential mediating mechanisms (experimental studies)

Background: The perioperative period often involves stress responses and surgery-induced hypothermia, which were suggested to hinder antimetastatic immunity and promote cancer metastasis. During this critical period, immunotherapies are rarely used, given contraindications to surgery. However, recent preclinical studies support the feasibility of perioperative TLR-9 activation using CpG-C. Materials and methods: Herein, we employed hypothermic-stress and normothermic-stress paradigms to assess their impact on perioperative CpG-C immune stimulation and resistance to experimental hepatic metastasis of CT26 colorectal cancer in BALB/c mice. Results: Perioperative hypothermic wet-cage stress markedly abrogated CpG-C-induced increase in plasma IL-12 levels, a persistent deleterious effect across different CpG-C doses and administration routes. These effects were not attenuated by blocking glucocorticoids, adrenergic, or opioid signaling, nor by adrenalectomy, suggesting a direct immunosuppressive impact of hypothermia on immunocytes. Indeed, normothermic wet-cage stress, which induced a similar corticosterone response, caused significantly less deleterious effects on IL-12 levels, hepatic NK cell maturation and cytotoxicity, and CT26 metastasis. Additionally, in-vitro exposure of PBMCs to 33°C markedly decreased CpG-C-induced IL-12 production. Last, two normothermic stress paradigms, tilt&light and restraint, did not jeopardize CpG-C-induced IL-12 response nor resistance to CT26 metastases. Interestingly, attenuating glucocorticoid signaling under tilt&light conditions improved CpG-C efficacy. Conclusions: Overall, these findings suggest that perioperative hypothermic stress can jeopardize antimetastatic immunity and resistance to metastasis, and prevent perioperative response to immune stimulation and its beneficial antimetastatic impacts, effects that are not mediated through classical neuroendocrine stress responses, but potentially through direct hypothermic impact on leukocytes. These findings may have clinical implications in operated cancer patients, many of whom suffer hypothermic stress.