Antitumour effect of the mitochondrial complex III inhibitor Atovaquone in combination with anti-PD-L1 therapy in mouse cancer models

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 imm...

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Bibliographic Details
Published in:Cell death & disease Vol. 15; no. 1; pp. 32 - 10
Main Authors: Rodriguez-Berriguete, Gonzalo, Puliyadi, Rathi, Machado, Nicole, Barberis, Alessandro, Prevo, Remko, McLaughlin, Martin, Buffa, Francesca M., Harrington, Kevin J., Higgins, Geoff S.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 11.01.2024
Springer Nature B.V
Nature Publishing Group
Subjects:
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Animal models
Animals
Antibodies
Atovaquone
Atovaquone - pharmacology
Atovaquone - therapeutic use
B7-H1 Antigen
Biochemistry
Biomedical and Life Sciences
Cancer
CD8 antigen
CD8-Positive T-Lymphocytes
Cell Biology
Cell Culture
Colorectal cancer
Colorectal carcinoma
Electron Transport Complex III
Humans
Hypoxia
Immune checkpoint inhibitors
Immunological memory
Immunology
Immunotherapy - methods
Life Sciences
Lung cancer
Lymphocytes T
Memory cells
Mice
Neoplasms - drug therapy
Oxygen consumption
PD-L1 protein
Toxicity
Tumor Microenvironment
Tumors
ISSN:2041-4889, 2041-4889
Online Access:Get full text
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Summary: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.
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ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-023-06405-8