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 t...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06405-8 |
| _version_ | 1797355433130721280 |
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| author | Gonzalo Rodriguez-Berriguete Rathi Puliyadi Nicole Machado Alessandro Barberis Remko Prevo Martin McLaughlin Francesca M. Buffa Kevin J. Harrington Geoff S. Higgins |
| author_facet | Gonzalo Rodriguez-Berriguete Rathi Puliyadi Nicole Machado Alessandro Barberis Remko Prevo Martin McLaughlin Francesca M. Buffa Kevin J. Harrington Geoff S. Higgins |
| author_sort | Gonzalo Rodriguez-Berriguete |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T14:12:07Z |
| format | Article |
| id | doaj.art-5dbc7022b8d548e28086316032aa0121 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-08T14:12:07Z |
| publishDate | 2024-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-5dbc7022b8d548e28086316032aa01212024-01-14T12:38:33ZengNature Publishing GroupCell Death and Disease2041-48892024-01-0115111010.1038/s41419-023-06405-8Antitumour effect of the mitochondrial complex III inhibitor Atovaquone in combination with anti-PD-L1 therapy in mouse cancer modelsGonzalo Rodriguez-Berriguete0Rathi Puliyadi1Nicole Machado2Alessandro Barberis3Remko Prevo4Martin McLaughlin5Francesca M. Buffa6Kevin J. Harrington7Geoff S. Higgins8Department of Oncology, University of OxfordDepartment of Oncology, University of OxfordDepartment of Oncology, University of OxfordNuffield Department of Surgical Sciences, University of OxfordDepartment of Oncology, University of OxfordInstitute of Cancer ResearchDepartment of Oncology, University of OxfordInstitute of Cancer ResearchDepartment of Oncology, University of OxfordAbstract 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.https://doi.org/10.1038/s41419-023-06405-8 |
| spellingShingle | Gonzalo Rodriguez-Berriguete Rathi Puliyadi Nicole Machado Alessandro Barberis Remko Prevo Martin McLaughlin Francesca M. Buffa Kevin J. Harrington Geoff S. Higgins Antitumour effect of the mitochondrial complex III inhibitor Atovaquone in combination with anti-PD-L1 therapy in mouse cancer models Cell Death and Disease |
| title | Antitumour effect of the mitochondrial complex III inhibitor Atovaquone in combination with anti-PD-L1 therapy in mouse cancer models |
| title_full | Antitumour effect of the mitochondrial complex III inhibitor Atovaquone in combination with anti-PD-L1 therapy in mouse cancer models |
| title_fullStr | Antitumour effect of the mitochondrial complex III inhibitor Atovaquone in combination with anti-PD-L1 therapy in mouse cancer models |
| title_full_unstemmed | Antitumour effect of the mitochondrial complex III inhibitor Atovaquone in combination with anti-PD-L1 therapy in mouse cancer models |
| title_short | Antitumour effect of the mitochondrial complex III inhibitor Atovaquone in combination with anti-PD-L1 therapy in mouse cancer models |
| title_sort | antitumour effect of the mitochondrial complex iii inhibitor atovaquone in combination with anti pd l1 therapy in mouse cancer models |
| url | https://doi.org/10.1038/s41419-023-06405-8 |
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