Intracranial tumors elicit systemic sympathetic hyperactivity that limits immunotherapeutic success

dc.contributor.advisor

Fecci, Peter E

dc.contributor.author

Lorrey, Selena

dc.date.accessioned

2025-01-08T17:44:03Z

dc.date.issued

2024

dc.department

Immunology

dc.description.abstract

Intracranial tumors present unique challenges for immunotherapy. These can include both local and systemic modes of immune suppression whose mechanistic underpinnings are incompletely understood. My PhD thesis reveals that intracranial tumors elicit systemic increases in circulating catecholamine levels and that resulting chronic sympathetic hyperactivity drives T cell dysfunction and limits immunotherapeutic success. Further, treatment with beta-adrenergic blockade can partially overcome such chronic sympathetic hypersensitivity, and results in increased NF-kB activity in immune cells, restored T cell polyfunctionality, tumor microenvironment modifications, and extended survival in murine models of glioblastoma (GBM) treated with immune-based therapies. We uncovered that extended survival is also observed in GBM patients that received beta-adrenergic blockade, as well as in patients with melanoma and lung cancer brain metastases who received beta-blockade alongside concomitant immune checkpoint inhibition. While beta-blockade also impacts outcomes in the setting of extracranial disease, the benefits are especially pronounced in patients harboring intracranial disease burdens. These data suggest that sympathetic hyperactivity facilitates systemic immune dysfunction in the setting of intracranial tumors, specifically and advance a role for beta-adrenergic blockade in licensing immunotherapeutic responses within the intracranial compartment.

dc.identifier.uri

https://hdl.handle.net/10161/31872

dc.rights.uri

https://creativecommons.org/licenses/by-nc-nd/4.0/

dc.subject

Immunology

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Medicine

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Oncology

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Cancer

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Glioblastoma

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Immunotherapy

dc.title

Intracranial tumors elicit systemic sympathetic hyperactivity that limits immunotherapeutic success

dc.type

Dissertation

duke.embargo.months

8

duke.embargo.release

2025-09-08T17:44:03Z

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