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A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response

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Abstract

Long conserved mechanisms maintain homeostasis in living creatures in response to a variety of stresses. However, continuous exposure to stress can result in unabated production of stress hormones, especially catecholamines, which can have detrimental health effects. While the long-term effects of chronic stress have well-known physiological consequences, recent discoveries have revealed that stress may affect therapeutic efficacy in cancer. Growing epidemiological evidence reveals strong correlations between progression-free and long-term survival and β-blocker usage in cancer patients. In this review, we summarize the current understanding of how the catecholamines, epinephrine and norepinephrine, affect cancer cell survival and tumor progression. We also highlight new data exploring the potential contributions of stress to immunosuppression in the tumor microenvironment and the implications of these findings for the efficacy of immunotherapies.

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Abbreviations

ADCC:

Antibody-dependent cell-mediated cytotoxicity

COX:

Cyclo-oxygenase

DC:

Dendritic cell

EGFR:

Epithelial growth factor receptor

EPI:

Epinephrine

IDO:

Indolamine-2,3-oxygenase

MAPK:

Mitogen-activated protein kinase

MDSC:

Myeloid-derived suppressor cell

NE:

Norepinephrine

NK:

Natural killer

PKA:

Protein kinase A

rhIL-2:

Recombinant human IL-2

SNS:

Sympathetic nervous system

TAM:

Tumor-associated macrophage

Treg :

Regulatory T cell

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Acknowledgments

We thank Jeanne Prendergast for editorial assistance. This work was supported by National Institute of Health Grants R01 CA135368 and T32 CA 085183 and Breast Cancer Research and Education Fund through NY State Department of Health contract # C028252.

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The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Jason W.-L. Eng, Kathleen M. Kokolus, Chelsey B. Reed, Bonnie L. Hylander & Elizabeth A. Repasky

  2. Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Wen W. Ma

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  1. Jason W.-L. Eng
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  2. Kathleen M. Kokolus
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Correspondence to Elizabeth A. Repasky.

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Eng, J.WL., Kokolus, K.M., Reed, C.B. et al. A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response. Cancer Immunol Immunother 63, 1115–1128 (2014). https://doi.org/10.1007/s00262-014-1617-9

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