Journal article
Tumour immune rejection triggered by activation of α2-adrenergic receptors
- Abstract:
-
Immunotherapy based on immunecheckpoint blockade (ICB) using antibodies induces rejection of tumours and brings clinical benefit in patients with various cancer types. However, tumours often resist immune rejection. Ongoing efforts trying to increase tumour response rates are based on combinations of ICB with compounds that aim to reduce immunosuppression in the tumour microenvironment but usually have little effect when used as monotherapies. Here we show that agonists of α2-adrenergic receptors (α2-AR) have very strong anti-tumour activity when used as monotherapies in multiple immunocompetent tumour models, including ICB-resistant models, but not in immunodeficient models. We also observed marked effects in human tumour xenografts implanted in mice reconstituted with human lymphocytes. The anti-tumour effects of α2-AR agonists were reverted by α2-AR antagonists, and were absent in Adra2a-knockout (encoding α2a-AR) mice, demonstrating on-target action exerted on host cells, not tumour cells. Tumours from treated mice contained increased infiltrating T lymphocytes and reduced myeloid suppressor cells, which were more apoptotic. Single-cell RNA-sequencing analysis revealed upregulation of innate and adaptive immune response pathways in macrophages and T cells. To exert their anti-tumour effects, α2-AR agonists required CD4+ T lymphocytes, CD8+ T lymphocytes and macrophages. Reconstitution studies in Adra2a-knockout mice indicated that the agonists acted directly on macrophages, increasing their ability to stimulate T lymphocytes. Our results indicate that α2-AR agonists, some of which are available clinically, could substantially improve the clinical efficacy of cancer immunotherapy.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
Actions
Access Document
- Files:
-
-
(Preview, Accepted manuscript, pdf, 3.9MB, Terms of use)
-
- Publisher copy:
- 10.1038/s41586-023-06110-8
Authors
- Publisher:
- Springer Nature
- Journal:
- Nature More from this journal
- Volume:
- 618
- Issue:
- 7965
- Pages:
- 607-615
- Publication date:
- 2023-06-07
- Acceptance date:
- 2023-04-20
- DOI:
- EISSN:
-
1476-4687
- ISSN:
-
0028-0836
- Pmid:
-
37286594
- Language:
-
English
- Keywords:
- Pubs id:
-
1369355
- Local pid:
-
pubs:1369355
- Deposit date:
-
2023-07-28
- ARK identifier:
Terms of use
- Copyright holder:
- Zhu et al.
- Copyright date:
- 2023
- Rights statement:
- © The Author(s), under exclusive licence to Springer Nature Limited 2023.
- Notes:
- This is the accepted manuscript version of the article. The final version is available online from Springer Nature at https://doi.org/10.1038/s41586-023-06110-8
If you are the owner of this record, you can report an update to it here: Report update to this record