Abstract
The ability of stress to induce immune suppression is widely recognized, but the mechanisms underlying the effects of stress on the adaptive immune system during tumor progression are not completely understood. To study the effect of stress on the immune system in vivo, we used a preclinical immunocompetent mouse model bearing 4T1 mammary adenocarcinoma cells. Mice were randomized into 4 groups, including social isolation (SI), acute restraint stress (aRRS), chronic restraint stress (cRRS), or no stress (NS). We found that SI significantly decreased the number of tumor-bearing mice still alive at the end of protocol (28 days), compared to NS mice. Although we did not detect significant changes in primary tumor volume, we observed a significant increase in the endothelial marker CD31 in primary tumors of SI mice and in lung metastases in SI and RRS mice. Survival decline in SI mice was associated with significant decreases in splenic CD8 cells and in activated T cells. From a mechanistic standpoint, RRS increased expression of FOXP3, CXCL-10, and granzyme B in mouse tumors, and the effects were reversed by propranolol. Our data demonstrate that various forms of stress differentially impact adaptive immunity and tumor angiogenesis, and negatively impact survival.
Highlights
Evidence supporting the predominant role of the immune system in cancer prognosis and clinical course of breast cancer is becoming increasingly apparent (Dieci et al, 2014; Ono et al, 2012)
To establish if different psychological stressors can affect the survival of tumor bearing mice, we examined the impact of three different stress regimens: acute restraint stress (aRRS), chronic restraint stress (cRRS), or social isolation (SI) in the 4T1 syngeneic mammary carcinoma model
We demonstrated that the duration and type of psychological stressors can differentially impact the adaptive immune system in an immunocompetent mouse model of triple negative breast cancer
Summary
Evidence supporting the predominant role of the immune system in cancer prognosis and clinical course of breast cancer is becoming increasingly apparent (Dieci et al, 2014; Ono et al, 2012). There has been increasing interest in detailing the mechanistic role that psychological stress may play in the context of initiation, progression, metastasis, and recurrence of breast cancer. The in vivo mechanisms by which chronic behavioral stress alters immune-effector (e.g., CD8+) and immune-suppressive T cells (e.g., Tregs), and thereby disease progression and recurrence, remain elusive. Because the beta-2 adrenergic receptor is believed to be the primary receptor on lymphocytes and a means through which the nervous system communicates with the immune system (Nakai, Hayano, Furuta, Noda, & Suzuki, 2014) and has been reported to prevent stress induced changes in ovarian cancer (Thaker et al, 2006) we assessed the impact of beta blockade on immune profiles in tumor bearing mice
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