Mounting preclinical and clinical evidence continues to support a role for the neuroendocrine system in the modulation of tumor biology and progression. Several studies have shown data supporting a link between chronic stress and cancer progression. Dysregulation of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in promoting angiogenesis, tumor cell proliferation and survival, alteration of the immune response and exacerbating inflammatory networks in the tumor microenvironment. Here, we review how SNS and HPA dysregulation contributes to disturbances in immune cell populations, modifies cancer biology, and impacts immunotherapy response. We also highlight several interventions aimed at circumventing the adverse effects stress has on cancer patients.

Multiple studies suggest that chronic stress accelerates the growth of existing tumors by activating the sympathetic nervous system. Data suggest that sustained adrenergic signaling can induce tumor growth, secretion of pro-inflammatory cytokines, and macrophage infiltration. Our goal was to study the role of adrenergic-stimulated macrophages in ovarian cancer biology. Cytokine arrays were used to assess the effect of adrenergic stimulation in pro-tumoral cytokine networks. An orthotopic model of ovarian cancer was used to assess the in vivo effect of daily restraint stress on tumor growth and adrenergic-induced macrophages. Cytokine analyses showed that adrenergic stimulation modulated pro-inflammatory cytokine secretion in a SKOV3ip1 ovarian cancer cell/U937 macrophage co-culture system. Among these, platelet-derived growth factor AA (PDGF-AA), epithelial cell-derived neutrophil-activating peptide (ENA-78), Angiogenin, vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-5 (IL-5), Lipocalin-2, macrophage migration inhibitory factor (MIF), and transferrin receptor (TfR) were upregulated. Enriched biological processes included cytokine-mediated signaling pathways and positive regulation of cell proliferation. In addition, daily restraint stress increased ovarian cancer growth, infiltration of CD68+ macrophages, and expression of PDGF-AA in orthotopic models of ovarian cancer (SKOV3ip1 and HeyT30), while zoledronic acid, a macrophage-depleting agent, abrogated this effect. Furthermore, in ovarian cancer patients, high PDGFA expression correlated with worse outcomes. Here, it is shown that the adrenergic regulation of macrophages and PDGFA might play a role in ovarian cancer progression.

Background: Mounting data suggest that exposure to chronic stress is associated with worse breast cancer outcomes. This study aimed to explore the impact of social environmental adversity (SEA, e.g., child abuse, crime, sexual, and physical violence), depressive symptomatology, and anxiety on immune cell infiltration into the breast tumor microenvironment. Methods: Participants (n = 33) completed a series of surveys assessing depression and anxiety symptoms, adverse childhood events (ACE), and trauma history. Tumor-associated macrophages (CD68+), B cells (CD19+), and T cells (CD3+) were identified by immunohistochemical analyses of formalin-fixed paraffin-embedded tumor samples and quantified. Spearman rank tests were used to explore the relationships between the variables studied. Results: Exposure to SEA was high (ACE = 72%, exposure to crime = 47%, and exposure to physical/sexual assault = 73%) among participants. Moreover, 30% reported a comorbid history of depression and ACE; 39% reported one or more traumatic events, and clinically significant depression symptomatology, while 21% reported trauma history and significant anxiety symptomatology. Increased tumor-infiltrating B cells were significantly correlated with exposure to crime, anxiety symptoms, and exposure to an ACE. The ACE plus anxiety group presented the highest infiltration of B cells, T cells, and macrophages. Conclusion: These findings support a role for SEA, anxiety symptoms, and depression as potential modulators of the immune tumor microenvironment in breast cancer.

A cancer diagnosis increases stress hormones levels and leads to altered psychological states. In the context of ovarian cancer (OC), chronic stress promotes tumor growth, chemoresistance and modulates immune cell populations in the tumor microenvironment (TME). Moreover, previous work from our team suggests that chronic stress promotes an increased inflammatory response in OC. Our data show an altered CD4+/CD8+ T-cell ratio and a heterogeneous expression of exhaustion markers in patients with high-grade serous ovarian cancer (HGSOC). Therefore, we hypothesized that chronic stress results in chronic inflammation and an immunosuppressed TME. To address this, we obtained ascites from 66 patients with HGSOC and measured cytokine levels using a comprehensive Cytokine/Chemokine immunoassay. Cortisol, corticosterone, and stress hormone metabolites (metanephrine and normetanephrine) levels from ascites were measured by ELISA. CD8+ T-cells isolated from OC patient ascites were stimulated with epinephrine, and flow cytometry was used to measure co-expression of CD38 activation marker and Granzyme B, an essential mediator of CD8+ T-cell killing capacity. To further establish the impact of chronic stress on tumor progression, we subjected IG10 or ID8 tumor-bearing C57/BL6 female mice to daily restraint stress. Mice were sacrificed 8-12 weeks after inoculation, data collected, and ascites stored. Results showed an increase in inflammatory cytokines (Eotaxin, IL-6, and IL-7) in recurrent tumors of HGSOC patients. IP-10 and IFN-γ were negatively associated with cortisol levels. Moreover, normetanephrine levels positively correlated with inflammatory cytokines: IL-6, MCP-1, MCP-3, VEGF, GRO, and IL-7. Metanephrine was also positively correlated with inflammatory cytokines: SCD40L, FGF-2, and MIP1α. Ascites-derived CD8+ T-cells treated with epinephrine showed decreased co-expression CD38 and Granzyme B. Additionally, data show that daily restraint stress led to increased tumor growth in ID8 and IG10 syngeneic mouse models of OC. Ascites derived from our animal models suggest a positive correlation of inflammatory cytokines VEGF, TNFα and Eotaxin, and corticosterone levels in ID8 tumor-bearing mice. These results suggest a role for stress hormones in inflammation and immunosuppression. In conclusion, inflammatory cytokines are upregulated in recurrent HGSOC ascites samples. Cytokines that regulate T-cell function were negatively associated with cortisol levels, while stress hormone metabolites correlated with higher inflammatory cytokines. Moreover, epinephrine stimulation decreased ascites-derived CD8+ T-cell function. Inflammatory cytokines correlated with corticosterone levels in ID8 tumor-bearing mice. Overall, these data suggest a role for chronic stress in inflammation and immunosuppression, impacting the efficacy of therapies that aim to restore T-cell function. Citation Format: Alexandra N. Aquino-Acevedo, Hope Knochenhauer, Melanie Ortiz-León, Yadiel A. Rivera-López, Margarita Bonilla-Claudio, John S. Yi, Rebecca A. Previs, Guillermo N. Armaiz-Pena. Chronic stress promotes tumor-associated inflammation in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2543.

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