Blockade of beta-adrenergic receptors reduces cancer growth and enhances the response to anti-CTLA4 therapy by modulating the tumor microenvironment

Klaire Yixin Fjæstad, Anne Mette Askehøj Rømer, Victor Goitea, Astrid Zedlitz Johansen, Marie Louise Thorseth, Marco Carretta, Lars Henning Engelholm, Lars Grøntved, Niels Junker, Daniel Hargbøl Madsen*

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Abstrakt

The development of immune checkpoint inhibitors (ICI) marks an important breakthrough of cancer therapies in the past years. However, only a limited fraction of patients benefit from such treatments, prompting the search for immune modulating agents that can improve the therapeutic efficacy. The nonselective beta blocker, propranolol, which for decades has been prescribed for the treatment of cardiovascular conditions, has recently been used successfully to treat metastatic angiosarcoma. These results have led to an orphan drug designation by the European Medicines Agency for the treatment of soft tissue sarcomas. The anti-tumor effects of propranolol are suggested to involve the reduction of cancer cell proliferation as well as angiogenesis. Here, we show that oral administration of propranolol delays tumor progression of MCA205 fibrosarcoma model and MC38 colon cancer model and increases the survival rate of tumor bearing mice. Propranolol works by reducing tumor angiogenesis and facilitating an anti-tumoral microenvironment with increased T cell infiltration and reduced infiltration of myeloid-derived suppressor cells (MDSCs). Using T cell deficient mice, we demonstrate that the full anti-tumor effect of propranolol requires the presence of T cells. Flow cytometry-based analysis and RNA sequencing of FACS-sorted cells show that propranolol treatment leads to an upregulation of PD-L1 on tumor associated macrophages (TAMs) and changes in their chemokine expression profile. Lastly, we observe that the co-administration of propranolol significantly enhances the efficacy of anti-CTLA4 therapy. Our results identify propranolol as an immune modulating agent, which can improve immune checkpoint inhibitor therapies in soft tissue sarcoma patients and potentially in other cancers.

OriginalsprogEngelsk
TidsskriftOncogene
Vol/bind41
Udgave nummer9
Sider (fra-til)1364-1375
ISSN0950-9232
DOI
StatusUdgivet - feb. 2022

Bibliografisk note

Funding Information:
This work was supported by the Lundbeck Foundation (R307-2018-3326) (to DHM), Danish Cancer Society (R231-A14035 and R231-A13832 (to DHM and LHE)), the Independent Research Fund Denmark (to LG), and department of Oncology, Herlev Hospital.

Publisher Copyright:
© 2022, The Author(s).

Fingeraftryk

Dyk ned i forskningsemnerne om 'Blockade of beta-adrenergic receptors reduces cancer growth and enhances the response to anti-CTLA4 therapy by modulating the tumor microenvironment'. Sammen danner de et unikt fingeraftryk.

Citationsformater