Psychological stress is associated with altered levels of myeloid-derived suppressor cells in breast cancer patients

https://doi.org/10.1016/j.cellimm.2011.04.003Get rights and content

Abstract

Our group has shown in a randomized clinical trial that psychological intervention to reduce stress in patients with stages II and III breast cancer led to enhanced immune function, fewer recurrences and improved overall survival. We hypothesized that patients with high levels of stress would have alterations in myeloid-derived suppressor cells (MDSC) compared to patients with lower stress. PBMC from 16 patients with high stress (n = 8) or with low stress (n = 8) after surgery as measured by the Impact of Event Scale (IES) questionnaire were evaluated for the presence of MDSC. Patients with higher IES scores had significantly elevated salivary cortisol levels (P = 0.013; 13 μg/dl vs. 9.74 μg/dl). Levels of IL-1Rα were also significantly elevated in the higher IES group (45.09 pg/ml vs. 97.16 pg/ml; P = 0.010). IP 10, G-CSF, and IL-6 were all higher in the high stress group although not to a significant degree. Flow cytometric analysis for CD33+/HLA-DR-neg/CD15+/CD11b+ MDSC revealed increased MDSC in patients with lower IES scores (P = 0.009). CD11b+/CD15+ cells constituted 9.4% of the CD33+/HLA DR-neg cell population in patients with high IES, vs. 27.3% in patients with low IES scores. Additional analyzes of the number of stressful events that affected the patients in addition to their cancer diagnosis revealed that this type of stress measure correlated with elevated levels of MDSC (P = 0.064). These data indicate the existence of a complex relationship between stress and immune function in breast cancer patients.

Introduction

The negative impact of stress on immune function is well established. Multiple studies have demonstrated that stressful events activate the hypothalamic–pituitary–adrenal axis which increases the production of hormones such as epinephrine, norepinephrine, and cortisol. Immune cells express receptors for these hormones and their function can be markedly altered by chronic exposure to these factors [1], [2], [3]. T cell cytokine production is shifted from Th1 towards a Th2 profile, and T cell proliferation and NK cell lysis is inhibited after chronic exposure of the organism to stress [1], [4]. Stress can also lead to alterations in systemic levels of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and interleukin-1 (IL 1), cytokines which are thought to be involved with tumor progression [5], [6], [7], [8], [9]. Additionally, these pro-inflammatory cytokines have been associated with the induction of suppressor cell populations that can further inhibit immune responses [10].

Myeloid-derived suppressor cells (MDSC) are a class of immune suppressor cells that are comprised of a heterogenous population of early myeloid cells. They are produced in the bone marrow from hematopoietic stem cells and represent less than 1% of circulating cells in normal individuals. MDSC are generally defined phenotypically as being positive for CD33+/CD11b+ (the common myeloid lineage and macrophage markers, respectively) and negative for other lineage markers [10]. Some investigators have further characterized subsets of MDSC as being negative for CD14, and positive for CD15 and IL 4Rα [11], [12], [13]. The apparent variety of MDSC subsets now being described could represent various stages of differentiation or functionally distinct cellular compartments.

MDSC are known to accumulate in patients with cancer and their numbers seem to correlate with tumor burden [14], [15], [16], [17]. The generation of MDSC in the bone marrow is believed to be enhanced in response to tumor-derived factors and these substances also promote the migration of MDSC from the bone marrow to the tumor site [10]. The available evidence strongly suggests that immune suppressor cells are able to blunt the ability of the innate and adaptive immune system to eliminate the developing tumor. The depletion of MDSC in murine models leads to a reduction in tumor growth and enhances the anti-tumor effects of immunotherapeutic regimens [18], [19], [20], [21]. MDSC use multiple different mechanisms to induce immune suppression. They produce nitric oxide which can inhibit immune cell signal transduction and they release arginase which depletes l-arginine from the tumor microenvironment, thus crippling T cell function [10], [13], [14], [22], [23]. In addition, they are known to produce reactive nitrogen and oxygen species that can further impair immune cell function [10], [13], [23], [24], [25], [26], [27], [28].

MDSC may represent a link between stress and cancer progression. It is known that stress leads to elevations in pro-inflammatory cytokines, and many of these stress induced factors are associated with the generation and/or expansion of MDSC [4]. However, the relationship between MDSC and stress has not been previously explored. A randomized clinical trial conducted by investigators at The Ohio State University found that a psychological intervention to reduce life stressors in surgically-treated breast cancer patients led to a significant reduction in recurrence, and an increase in overall survival [29]. Further, these positive outcomes were associated with improved function of immune cells as measured by NK cell cytotoxicity and T cell proliferation [30]. Based on these observations, we hypothesized that high levels of chronic stress would be associated with increased levels of stress hormones and cytokines that in turn would stimulate the generation and accumulation of MDSC. These suppressor cells are known to negatively impact immune function and could theoretically have led to the decrease in breast cancer survival as was seen in the clinical trial.

To evaluate this hypothesis, we examined patients with high or low stress as measured by the Impact of Event Scale (IES) to determine the relationship between cancer stress, stress hormones, pro inflammatory cytokines, and MDSC levels in stages II and III breast cancer patients who were post-surgery and awaiting the start of adjuvant therapy.

Section snippets

Patients

Patients with stage II or III breast cancer were recruited for a randomized trial studying the effects of a structured psychological intervention on breast cancer recurrence and overall survival. Blood and saliva samples were taken from patients post-surgery and prior to the initiation of adjuvant therapy. This study describes baseline data, prior to any psychological intervention for a subset of trial participants (n = 16). All samples were obtained under an Institutional Review Board-approved

Hormones, pro-inflammatory cytokines and stress

Chronic stress is associated with increases in cytokines which are known to have effects on MDSC generation and expansion. To delineate two different patient stress groups, patients with higher or lower than the average cancer-specific stress IES score (20–30) were chosen for study (Table 1; n = 16; P = 0.001). Stress hormone levels were evaluated in the high and low IES groups to determine the relationship between these two factors. Salivary cortisol levels were significantly elevated in the high

Discussion

This study was initiated to evaluate the effects of cancer-specific stress on MDSC levels in post-surgical breast cancer patients. Patients at the two extreme ends of the IES scale were selected for evaluation. Those with below average scores were designated as the low IES group while those with elevated scores were designated as the high IES group. Cortisol and IL-1Rα were significantly elevated in the high IES group as compared to the low IES group. Low IES patients had significantly elevated

Acknowledgments

These projects have been funded by the following granting agencies: National Institutes of Health (NIH) Grants T32 GM068412 (to B. Mundy), P01 CA95426, K24 CA93670 (to W.E. Carson), American Cancer Society (PBR-89, RSGPB-03-248-01-PBP; PF-07-169-01-CPPB), Longaberger Company-American Cancer Society Grant for Breast Cancer Research (PBR-89A), US Army Medical Research Acquisition Activity Grants (DAMD17-94-J-4165; DAMD17-96-1-6294; DAMD17-97-1-7062), National Institutes of Mental Health (R01

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