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Stress Upregulates Suppressor Cells in Breast Cancer

Stress – Suppressor Cells in Breast Cancer

Update at BrainImmuneA new study in Cellular Immunology is perhaps the first to specifically measure levels of myeloid-derived suppressor cells (MDSC) in post operative breast cancer patients who were considered to be macroscopically disease-free.

In this study, Bethany Mundy-Bosse and colleagues from the Department of Integrated Biomedical Sciences, the Ohio State University, Columbus OH investigated the association between psychological stress and MDSC levels in post-surgical breast cancer patients.

Myeloid-derived suppressor cells (MDSC) are a class of immune suppressor cells that represent less than 1% of circulating cells in normal individuals. These newly identified immature myeloid cells are characterized by the ability to suppress immune responses and expand during cancer, infection, and inflammatory diseases. These cells are known to accumulate in patients with cancer and their numbers seem to correlate with tumor burden.

The generation of MDSC in the bone marrow and the migration of MDSC from the bone marrow to the tumor site are enhanced in response to tumor-derived factors. Research evidence indicates that immune suppressor cells are able to reduce the ability of the innate and adaptive immune system to eliminate the developing tumor.

Recent epidemiological, fundamental and clinical studies also indicate that psychological stress is implicated in the development and progression of cancer.

In the Cellular Immunology study Bethany Mundy-Bosse et al. report that when study participants were evaluated for objective, longer-term stressors by the Life Events measure of stress, patients with higher stress levels exhibited higher baseline numbers of MDSC.

According to the authors, further studies are warranted to evaluate the direct effects of MDSC on natural killer (NK) and T cell function and how stress may alter these interactions. Along these lines, this study further supports the existence of a complex relationship between stress and immune function in breast cancer patients.

SOURCE:  Cell Immunol, 2011, 270:80. Epub 2011 Apr 23.

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A 2016 study indicates that chronic psychosocial stress in mice not only increases the number of  MDSC and Treg cells, but in the case of MDSC also enhances their suppressive capacity. It appears that catecholaminergic and TNF signaling are involved in these changes. The authors of this study discuss that this supports the idea of promotion of tumor growth by chronic psychosocial stress. Thus, stress-induced “emergency myelopoiesis” might promote increased innate immune activation, but may also set the stage for promoted tumor growth.

A 2019 study indicates that chronic restraint stress promotes hepatocellular carcinoma growth by mobilizing splenic myeloid cells to tumor tissues via activating β-adrenergic signaling.

In a 2021 study chronic restraint stress paradigm was applied to the H22 hepatocellular carcinoma (HCC) bearing mice to mimic the psychological stress. The authors found that chronic restraint stress significantly promoted HCC growth, as well as the mobilization of MDSCs to spleen and tumor sites from bone marrow.

This study provides evidence that catecholamines mediate the mobilization and immunosuppressive function of MDSCs via CXCL5-CXCR2-Erk signaling, linking psychological stress with the enhanced tumor progression. The nonselective antagonist of β-AR, propranolol, almost completely abrogated the efficacy of chronic stress in H22 tumor model.

In conclusion, these results demonstrate that β-adrenergic signaling plays a crucial role in tumor progression induced by chronic restraint stress and CXCL5-CXCR2-Erk activation enhances the immunosuppressive function and mobilization of MDSCs.

Another 2021 study indicates that the pre-exposure of chronic stress contributes to MDSCs elevation and facilitated breast cancer metastasis in tumor-bearing mice.

The study revealed that the expressions of IL-6 and JAK/STAT3 signaling pathways were upregulated by chronic stress in mice, and this upregulation could be inhibited by propranolol. Blocking the IL-6 signal or inhibiting the activation of the JAK/STAT3 signaling pathway could reduce tumor growth and metastasis by attenuating the accumulation of MDSCs in vivo. Moreover, the authors found that tumor-derived IL-6 promoted the differentiation of MDSCs in vitro and there was a positive correlation between the expression of IL-6 and the percentage of MDSCs

Also, propranolol could prevent tumor metastasis and the increase of MDSCs induced by CUS. Importantly, blocking the IL-6 signal or inhibiting the activation of the JAK/STAT signaling pathway could reduce tumor metastasis by attenuating the accumulation MDSCs.

Taken together, these data indicated that chronic stress may accumulate MDSCs via activation of β-adrenergic signaling and IL-6/STAT3 pathway, thereby promoting breast carcinoma metastasis (see Figure 1).

stress MDSCFigure 1. Chronic stress causes the sympathetic nerve to release norepinephrine (NE). High levels of NE induce tumor cells to secrete large amount of IL-6 through β2-adrenergic receptor signal pathway. IL-6 promotes MDSCs differentiation by activating IL-6/STAT3 signal pathway. Increased MDSCs promotes lung metastasis of breast cancer. From: Chronic stress promotes breast carcinoma metastasis by accumulating myeloid-derived suppressor cells through activating β-adrenergic signalling, by Jiale an et al. Oncoimmunology, 2021 Nov 23;10. Open Access. Public Domain.

The authors of this study discuss that the sympathetic nerves regulation of MDSCs mobilization may provide potential cellular and molecular mechanisms for clinical studies linking chronic stress to increased breast cancer progression in humans. Of note, in this model, stress-induced activation of the sympathetic nervous system (SNS) showed moderately fast tumor growth of primary tumors, but reliably enhanced metastatic spread in the lung!

Also, MDSCs may represent a key link between chronic stress and tumor progression since many proinflammatory cytokines induced by chronic stress are associated with the generation and/or expansion of MDSCs.

In conclusion, this study revealed that chronic psychological stress upregulated the levels of proinflammatory cytokines, stimulated MDSCs accumulation, and promoted lung MDSCs infiltration through catecholamine-mediated β-adrenergic signaling in breast tumor-bearing mice.

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Cover Image Credit: Myeloid-derived suppressor cells; Immunology News: Targeting Myeloid-Derived Suppressor Cells (MDSCs) for Cancer Immunotherapy: