Journal article
Antitumour effect of the mitochondrial complex III inhibitor Atovaquone in combination with anti-PD-L1 therapy in mouse cancer models
- Abstract:
- Immune checkpoint blockade (ICB) provides effective and durable responses for several tumour types by unleashing an immune response directed against cancer cells. However, a substantial number of patients treated with ICB develop relapse or do not respond, which has been partly attributed to the immune-suppressive effect of tumour hypoxia. We have previously demonstrated that the mitochondrial complex III inhibitor atovaquone alleviates tumour hypoxia both in human xenografts and in cancer patients by decreasing oxygen consumption and consequently increasing oxygen availability in the tumour. Here, we show that atovaquone alleviates hypoxia and synergises with the ICB antibody anti-PD-L1, significantly improving the rates of tumour eradication in the syngeneic CT26 model of colorectal cancer. The synergistic effect between atovaquone and anti-PD-L1 relied on CD8+ T cells, resulted in the establishment of a tumour-specific memory immune response, and was not associated with any toxicity. We also tested atovaquone in combination with anti-PD-L1 in the LLC (lung) and MC38 (colorectal) cancer syngeneic models but, despite causing a considerable reduction in tumour hypoxia, atovaquone did not add any therapeutic benefit to ICB in these models. These results suggest that atovaquone has the potential to improve the outcomes of patients treated with ICB, but predictive biomarkers are required to identify individuals likely to benefit from this intervention.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 2.4MB, Terms of use)
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- Publisher copy:
- 10.1038/s41419-023-06405-8
Authors
+ Cancer Research UK
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- Funder identifier:
- https://ror.org/054225q67
- Grant:
- C34326/A19590
- C5255/A18085
- C6078/A28736
- 27515
- 23969
+ Department of Health and Social Care
More from this funder
- Funder identifier:
- https://ror.org/03sbpja79
- Publisher:
- Springer Nature
- Journal:
- Cell Death & Disease More from this journal
- Volume:
- 15
- Issue:
- 1
- Article number:
- 32
- Place of publication:
- England
- Publication date:
- 2024-01-11
- Acceptance date:
- 2023-12-20
- DOI:
- EISSN:
-
2041-4889
- Pmid:
-
38212297
- Language:
-
English
- Pubs id:
-
1598781
- Local pid:
-
pubs:1598781
- Source identifiers:
-
W4390755111
- Deposit date:
-
2026-04-28
- ARK identifier:
Terms of use
- Copyright holder:
- Rodriguez-Berriguete et al.
- Copyright date:
- 2024
- Rights statement:
- © The Author(s) 2024. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
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