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Cited by 35Cancer, Stress, Anesthesia, and Immune ResponseImmune cells in cancerStress Responses and Cortisol

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Investigating the crosstalk between chronic stress and immune cells: implications for enhanced cancer therapy

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Lei, YongRong, Liao, Fenghui, Tian, YiChen, Wang, YaNi, Xia, Feng, Wang, JianHua·2023·Frontiers in Neuroscience
DOI 10.3389/fnins.2023.1321176PMC PMC10713832
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Abstract

Chronic stress has a substantial influence on the tumor microenvironment (TME), leading to compromised effectiveness of anti-cancer therapies through diverse mechanisms. It disrupts vital functions of immune cells that play a critical role in anti-tumor immunity, such as the inhibition of dendritic cells (DCs) and lymphocytes, while simultaneously enhancing the activity of immune cells that support tumor growth, such as myeloid-derived suppressor cells and tumor-associated macrophages. Furthermore, chronic stress exerts a significant impact on crucial mechanisms within the TME, including angiogenesis, DNA repair, hypoxia, extracellular matrix deposition, and tumor metabolism. These alterations in the TME, induced by stress, result from the activation of the hypothalamic–pituitary–adrenal axis and sympathetic nervous system, in conjunction with epigenetic modifications. In conclusion, chronic stress significantly influences the TME and impedes the efficacy of anti-cancer treatments, underscoring the importance of targeting stress pathways to improve therapeutic results.

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Crossref · 10.3389/fnins.2023.1321176

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Figure 1 Chronic stress exerts a significant influence on the TME by primarily activating essential neuroendocrine response systems, namely the SNS and the HPA axis. The activation of the SNS leads to the secretion of NE and facilitates the synthesis and release of adrenaline and noradrenaline. However, the activation of the HPA axis results in the release of CRH from the hypothalamus, which in turn stimulates the secretion of adrenocorticotropic hormone ACTH and glucocorticoids (GCs) from the pituitary gland. It is worth noting that this complex cascade plays a significant role in facilitating the secretion and release of GCs from the adrenal cortex. Furthermore, the impact of stress-related hormones on cancer cells is mediated through their interaction with receptors on immune cells, thereby facilitating crucial biological processes including cell survival, programmed cell death, cellular self-degradation, cell division, cellular movement, and infiltration.
Figure 1 Chronic stress exerts a significant influence on the TME by primarily activating essential neuroendocrine response systems, namely the SNS and the HPA axis. The activation of the SNS leads to the secretion of NE and facilitates the synthesis and release of adrenaline and noradrenaline. However, the activation of the HPA axis results in the release of CRH from the hypothalamus, which in turn stimulates the secretion of adrenocorticotropic hormone ACTH and glucocorticoids (GCs) from the pituitary gland. It is worth noting that this complex cascade plays a significant role in facilitating the secretion and release of GCs from the adrenal cortex. Furthermore, the impact of stress-related hormones on cancer cells is mediated through their interaction with receptors on immune cells, thereby facilitating crucial biological processes including cell survival, programmed cell death, cellular self-degradation, cell division, cellular movement, and infiltration.CC BY · PubMed Central
Figure 2 This study provides evidence that chronic stress induces the activation of a signaling pathway that significantly impacts the TME. ARs, specifically α-AR, β2-AR, and β3-AR, play a crucial role in this process. ARs function as G-protein coupled receptors (GPCRs) and bind to agonists such as adrenaline and noradrenaline. This binding activates intracellular Gαs protein, initiating a series of reactions that result in increased levels of intracellular IP3, DAG, and cAMP. Additionally, this activation simultaneously triggers second messenger pathways, including PKA, PKC, EPAC, and Ca2+-CaM. Furthermore, the involvement of glucocorticoid receptors (GRs), which are part of the nuclear receptor family, is also noteworthy. When GCs permeate the cell membrane and bind to GRs, the Hsp protein dissociates, enabling the primary subunit of GRs to relocate to the cell nucleus and initiate gene transcription. Consequently, the regulation of cytokine and ligand gene expression occurs, thereby impacting protein synthesis programming and epigenetic gene expression. Collectively, these signaling mechanisms induce changes that contribute to the deterioration of the TME and ultimately promote tumor development. E, Epinephrine; EPAC, Exchange protein directly activated by cAMP; DAG, Diacylglycerol; ERK, Extracellular signal-regulated kinase; PI3K, Phosphatidylinositol 3-kinase; Hsp., Heat shock protein; PKA, Protein kinase A; AC, Adenylyl cyclase; MDR, Multidrug resistance; GATA1, GATA-binding protein 1; STAT3, Signal transducer and activator of transcription 3; NE, Norepinephrine; CaM, Calmodulin; IP3, Inositol trisphosphate; PIP2, Phosphatidylinositol 4,5-bisphosphate; EMT, Epithelial-mesenchymal transition; PKC, Protein kinase C; PLC, Phospholipase C; CREB, cAMP response element-binding protein; GR, Glucocorticoid receptor; CTL, Cytotoxic T lymphocyte; ECM, Extracellular matrix; NKCC, NK cell cytotoxicity; IFN, Interferon; ATP, Adenosine triphosphate; cAMP, Cyclic adenosine monophosphate; MEK, Mitogen-activated protein kinase; Pap1, Pathway activator protein 1.
Figure 2 This study provides evidence that chronic stress induces the activation of a signaling pathway that significantly impacts the TME. ARs, specifically α-AR, β2-AR, and β3-AR, play a crucial role in this process. ARs function as G-protein coupled receptors (GPCRs) and bind to agonists such as adrenaline and noradrenaline. This binding activates intracellular Gαs protein, initiating a series of reactions that result in increased levels of intracellular IP3, DAG, and cAMP. Additionally, this activation simultaneously triggers second messenger pathways, including PKA, PKC, EPAC, and Ca2+-CaM. Furthermore, the involvement of glucocorticoid receptors (GRs), which are part of the nuclear receptor family, is also noteworthy. When GCs permeate the cell membrane and bind to GRs, the Hsp protein dissociates, enabling the primary subunit of GRs to relocate to the cell nucleus and initiate gene transcription. Consequently, the regulation of cytokine and ligand gene expression occurs, thereby impacting protein synthesis programming and epigenetic gene expression. Collectively, these signaling mechanisms induce changes that contribute to the deterioration of the TME and ultimately promote tumor development. E, Epinephrine; EPAC, Exchange protein directly activated by cAMP; DAG, Diacylglycerol; ERK, Extracellular signal-regulated kinase; PI3K, Phosphatidylinositol 3-kinase; Hsp., Heat shock protein; PKA, Protein kinase A; AC, Adenylyl cyclase; MDR, Multidrug resistance; GATA1, GATA-binding protein 1; STAT3, Signal transducer and activator of transcription 3; NE, Norepinephrine; CaM, Calmodulin; IP3, Inositol trisphosphate; PIP2, Phosphatidylinositol 4,5-bisphosphate; EMT, Epithelial-mesenchymal transition; PKC, Protein kinase C; PLC, Phospholipase C; CREB, cAMP response element-binding protein; GR, Glucocorticoid receptor; CTL, Cytotoxic T lymphocyte; ECM, Extracellular matrix; NKCC, NK cell cytotoxicity; IFN, Interferon; ATP, Adenosine triphosphate; cAMP, Cyclic adenosine monophosphate; MEK, Mitogen-activated protein kinase; Pap1, Pathway activator protein 1.CC BY · PubMed Central
Figure 3 There are several strategies that can be implemented to mitigate the advancement of cancer resulting from chronic stress. These strategies encompass the use of targeted inhibitors, psychosocial interventions, neurofiber therapy, receptor blockers (including both β-ARs and α-ARs blockers), modulation of gut microbiota, modulation of the immune system, and the incorporation of traditional Chinese medicine. Targeted inhibitors encompass the utilization of pharmacological compounds, protein inhibitors, and other substances that specifically target metabolic processes. Psychosocial interventions encompass a diverse array of activities, including aerobic exercise, psychotherapy, yoga therapy, music therapy, and mindfulness training. Neurofiber therapy incorporates a multitude of treatment modalities, such as nerve ablation, inhibition of nerve growth factor, and interventions for anti-neural diseases. The classification of β-ARs blockers includes subcategories such as β2-AR blockers and β3-AR blockers, whereas α-ARs blockers encompass both α2-AR blockers and α1-AR blockers.
Figure 3 There are several strategies that can be implemented to mitigate the advancement of cancer resulting from chronic stress. These strategies encompass the use of targeted inhibitors, psychosocial interventions, neurofiber therapy, receptor blockers (including both β-ARs and α-ARs blockers), modulation of gut microbiota, modulation of the immune system, and the incorporation of traditional Chinese medicine. Targeted inhibitors encompass the utilization of pharmacological compounds, protein inhibitors, and other substances that specifically target metabolic processes. Psychosocial interventions encompass a diverse array of activities, including aerobic exercise, psychotherapy, yoga therapy, music therapy, and mindfulness training. Neurofiber therapy incorporates a multitude of treatment modalities, such as nerve ablation, inhibition of nerve growth factor, and interventions for anti-neural diseases. The classification of β-ARs blockers includes subcategories such as β2-AR blockers and β3-AR blockers, whereas α-ARs blockers encompass both α2-AR blockers and α1-AR blockers.CC BY · PubMed Central

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Metadata

Authors
Lei, Y., Liao, F., Tian, Y., Wang, Y., Xia, F., & Wang, J.
Affiliations
  • Army Medical University (CN)
  • Chongqing University (CN)
Corresponding author
  • Xia, Feng
  • Wang, JianHua
ORCID
Wang, JianHua
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2023-11-28
Volume
17
Pages
1321176-1321176
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2023.1321176
PMC
PMC10713832
OpenAlex
W4389095810
Cited by
35
References
230
Citations by year
2026: 17 · 2025: 12 · 2024: 6
FWCI
1.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (21827812)
  • Centre Scientifique et Technique du Bâtiment
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Stress, Anesthesia, and Immune Response
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
chronic stress, tumor microenvironment, antitumor immunity, dendritic cells, lymphocytes, myeloid-derived suppressor cells, tumor-associated macrophages, angiogenesis, DNA repair, hypoxia, extracellular matrix, cancer metabolism, hypothalamic-pituitary-adrenal axis, sympathetic nervous system, epigenetic modifications, cancer therapy resistance

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