Chronic stress-induced immune dysregulation in cancer: implications for initiation, progression, metastasis, and treatment

Abstract

Psychological stress is a well-accepted risk factor in cancer initiation and progression. The explosive growth of psychoneuroimmunology research in the past decade has yielded an unprecedented wealth of information about the critical role of chronic stress in the immune dysfunction that influences tumor behaviors, which presents insights to mitigate distress and improve prognosis in cancer patients. Chronic stress exacerbates inflammation and causes a metabolism disorder, making it difficult for the organisms to maintain homeostasis and increasing its susceptibility to cancer. The shifted differentiation and redistribution of the immune system induced by chronic stress fail to combat cancer efficiently. Chronic stress increases the tumor-educated immune suppressive cells and impairs the cytotoxicity of cellular immunity, thereby promoting lymphatic metastasis and hematogenous metastasis. In addition, the efficacy of existing cancer therapies is undermined because chronic stress prevents the immune system from responding properly. Emerging stress-reduction measures have been administered to assist cancer patients to cope with the adverse effects of chronic stress. Here we systematically review the current molecular, cellular, physiological mechanisms about stress-mediated immune responses in the enhancement of tumor initiation and progression, remodeling of tumor microenvironment and impairment of anti-tumor treatment. We also summarize the potential clinically applicable stress-oriented strategies towards cancer and discuss briefly where important knowledge gaps remain.

Keywords: Tumor immunology; anti-cancer therapy; biobehavioral sciences; psychological distress; tumor microenvironment.

Figure 1

Chronic stress aggravates inflammation-mediated intestinal barrier dysfunction and promotes colitis-associated tumorigenesis. In DSS and AOM treated murine colitis model, chronic stress increases mast cell degranulation by activating CRF1 signaling. It also increases the infiltration of monocytes, neutrophils, and macrophages, which produces pro-inflammatory cytokines like IL-1β, IL-6, and TNF-α and increases the activity of MPO. In the meantime, microbiota disorder is observed with an increase in inflammation-promoting operational taxonomic units. The inflammatory environment is observed with more ROS, leading to the increased permeability of bacteria and macromolecules and depletion of mucus. The intensified colitis in chronic stress is related to the higher incidence of colitis-associated tumorigenesis. Abbreviations: DSS, dextran sodium sulfate; AOM, azoxymethane; MPO, myeloperoxidase; CRF1, Corticotropin-releasing factor receptor subtype 1 (CRF1); IL-1β, Interleukin-1 beta; IL-6, Interleukin-6; TNF-α, tumor necrosis factor (TNF)-α; ROS, reactive oxygen species.

Figure 2

Chronic stress plays multiple roles in tumor progression and metastasis. Stress increases myelopoiesis and spleen mass. The expanded macrophages, MDSCs, and monocytes migrate into the TME due to the increased expressions of chemokines including CCL2, CXCL2, and CXCL3. Stress also alters the composition of immune cells in the TME. The number of M2-like TAM, immature DC, MDSC, and Treg increases, which produces more IL-10, NO2, VEGF, PGE2, and MMP9. At the same time, stress changes the metabolic pattern by increasing the expression of LDHA and promoting glycolysis, which creates an immunosuppressive microenvironment. In addition, stress increases the lymphatic metastasis and hematogenous metastasis. Stress activates macrophages to express more COX2 and produce more PGE2, which is a prerequisite for tumor lymphatic remodeling and tumor cell dissemination. Monocytes/macrophages have been recruited to the lungs and form a pre-metastatic niche for the subsequent arrival of disseminated tumor cells via the CCR2-CCL2 axis. Besides, the NK cell cytotoxicity has been impaired. Chronic stress also increases the secretion of the pro-inflammatory cytokines in microglia cells and macrophages, which impairs the integrity of the blood-brain barrier and increases the survival chance of disseminated tumor cells in the brain. Abbreviations: TME, tumor microenvironment; COX2, cyclooxygenase 2; MDSC, myeloid-derived suppressor cell; CCL2, C-C motif chemokine ligand 2; CXCL2, (C-X-C motif) ligand 2; CXCL3, (C-X-C motif) ligand 3; DC, dendritic cell; TAM, tumor-associated macrophage; Treg, regulatory T cell; IL-10, Interleukin-10; VEGF, vascular endothelial growth factor; PGE2, prostaglandin E2; MMP9, matrix metalloproteinase 9; IL-1β, Interleukin-1 beta; IL-6, Interleukin-6; TNF-α, tumor necrosis factor (TNF)-α; ROS, reactive oxygen species; GF, growth factor; FAS, fatty acid synthase; LDHA, lactate dehydrogenase A; COX2, cyclooxygenase 2; CCR2, CC chemokine receptor 2; NK, natural killer; CTL, cytotoxic T lymphocyte; FAS, fatty acid synthase.

Figure 3

Chronic stress weakens the therapeutic responses of anti-tumor therapies. Chronic stress impairs the maturation, antigen presentation, and migration of DCs, which fails to initiate CD8⁺ T cell activation and IFN-γ secretion. Chronic stress also blunts CTLs by increasing PD-1 expression and decreasing IL-2 receptor expression, resulting in lower production of IFN-γ and IL-2. The stress-induced malfunction of the immune system weakens the efficacy of anti-cancer therapies and promotes tumor progression. Abbreviations: DC, dendritic cell; IFN-γ, interferon γ; CTL, cytotoxic T lymphocyte; PD-1, programmed death receptor-1; IL-2, Interleukin-2.