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Qiao G, Chen M, Mohammadpour H, et al. Chronic Adrenergic Stress Contributes to Metabolic Dysfunction and an Exhausted Phenotype in T Cells in the Tumor Microenvironment. Cancer Immunol Res. 2021;9(6):651-664doi: 10.1158/2326-6066.CIR-20-0445.
Qiao, G., Chen, M., Mohammadpour, H., MacDonald, C. R., Bucsek, M. J., Hylander, B. L., Barbi, J. J., & Repasky, E. A. (2021). Chronic Adrenergic Stress Contributes to Metabolic Dysfunction and an Exhausted Phenotype in T Cells in the Tumor Microenvironment. Cancer immunology research, 9(6), 651-664. https://doi.org/10.1158/2326-6066.CIR-20-0445
Qiao, Guanxi, et al. "Chronic Adrenergic Stress Contributes to Metabolic Dysfunction and an Exhausted Phenotype in T Cells in the Tumor Microenvironment." Cancer immunology research vol. 9,6 (2021): 651-664. doi: https://doi.org/10.1158/2326-6066.CIR-20-0445
Qiao G, Chen M, Mohammadpour H, MacDonald CR, Bucsek MJ, Hylander BL, Barbi JJ, Repasky EA. Chronic Adrenergic Stress Contributes to Metabolic Dysfunction and an Exhausted Phenotype in T Cells in the Tumor Microenvironment. Cancer Immunol Res. 2021 Jun;9(6):651-664. doi: 10.1158/2326-6066.CIR-20-0445. Epub 2021 Mar 24. PMID: 33762351; PMCID: PMC8355045.
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Cancer Immunol Res. 2021 Jun;9(6):651-664. doi: 10.1158/2326-6066.CIR-20-0445. Epub 2021 Mar 24.

Chronic Adrenergic Stress Contributes to Metabolic Dysfunction and an Exhausted Phenotype in T Cells in the Tumor Microenvironment.

Cancer immunology research

Guanxi Qiao, Minhui Chen, Hemn Mohammadpour, Cameron R MacDonald, Mark J Bucsek, Bonnie L Hylander, Joseph J Barbi, Elizabeth A Repasky

Affiliations

  1. Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
  2. Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York. [email protected].

PMID: 33762351 PMCID: PMC8355045 DOI: 10.1158/2326-6066.CIR-20-0445

Abstract

Metabolic dysfunction and exhaustion in tumor-infiltrating T cells have been linked to ineffectual antitumor immunity and the failure of immune checkpoint inhibitor therapy. We report here that chronic stress plays a previously unrecognized role in regulating the state of T cells in the tumor microenvironment (TME). Using two mouse tumor models, we found that blocking chronic adrenergic stress signaling using the pan β-blocker propranolol or by using mice lacking the β2-adrenergic receptor (β2-AR) results in reduced tumor growth rates with significantly fewer tumor-infiltrating T cells that express markers of exhaustion, with a concomitant increase in progenitor exhausted T cells. We also report that blocking β-AR signaling in mice increases glycolysis and oxidative phosphorylation in tumor-infiltrating lymphocytes (TIL), which associated with increased expression of the costimulatory molecule CD28 and increased antitumor effector functions, including increased cytokine production. Using T cells from Nur77-GFP reporter mice to monitor T-cell activation, we observed that stress-induced β-AR signaling suppresses T-cell receptor (TCR) signaling. Together, these data suggest that chronic stress-induced adrenergic receptor signaling serves as a "checkpoint" of immune responses and contributes to immunosuppression in the TME by promoting T-cell metabolic dysfunction and exhaustion. These results also support the possibility that chronic stress, which unfortunately is increased in many patients with cancer following their diagnoses, could be exerting a major negative influence on the outcome of therapies that depend upon the status of TILs and support the use of strategies to reduce stress or β-AR signaling in combination with immunotherapy.

©2021 American Association for Cancer Research.

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