CD47-SIRPα Checkpoint Disruption in Metastases Requires Tumor-Targeting Antibody for Molecular and Engineered Macrophage Therapies
The macrophage checkpoint interaction CD47-SIRPα is an emerging target for cancer therapy, but clinical trials of monoclonal anti-CD47 show efficacy only in liquid tumors when combined with tumor-opsonizing IgG. Here, in challenging metastatic solid tumors, CD47 deletion shows no effect on tumor gro...
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-04-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/14/8/1930 |
| _version_ | 1797436526883241984 |
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| author | Jason C. Andrechak Lawrence J. Dooling Michael P. Tobin William Zhang Brandon H. Hayes Justine Y. Lee Xiaoling Jin Jerome Irianto Dennis E. Discher |
| author_facet | Jason C. Andrechak Lawrence J. Dooling Michael P. Tobin William Zhang Brandon H. Hayes Justine Y. Lee Xiaoling Jin Jerome Irianto Dennis E. Discher |
| author_sort | Jason C. Andrechak |
| collection | DOAJ |
| description | The macrophage checkpoint interaction CD47-SIRPα is an emerging target for cancer therapy, but clinical trials of monoclonal anti-CD47 show efficacy only in liquid tumors when combined with tumor-opsonizing IgG. Here, in challenging metastatic solid tumors, CD47 deletion shows no effect on tumor growth unless combined with otherwise ineffective tumor-opsonization, and we likewise show wild-type metastases are suppressed by SIRPα-blocked macrophages plus tumor-opsonization. Lung tumor nodules of syngeneic B16F10 melanoma cells with CD47 deletion show opsonization drives macrophage phagocytosis of B16F10s, consistent with growth versus phagocytosis calculus for exponential suppression of cancer. Wild-type CD47 levels on metastases in lungs of immunocompetent mice and on human metastases in livers of immunodeficient mice show that systemic injection of antibody-engineered macrophages also suppresses growth. Such in vivo functionality can be modulated by particle pre-loading of the macrophages. Thus, even though CD47-SIRPα disruption and tumor-opsonizing IgG are separately ineffective against established metastatic solid tumors, their combination in molecular and cellular therapies prolongs survival. |
| first_indexed | 2024-03-09T11:03:02Z |
| format | Article |
| id | doaj.art-1eda1536bd4f437b8d93508dbb58b289 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T11:03:02Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-1eda1536bd4f437b8d93508dbb58b2892023-12-01T01:06:05ZengMDPI AGCancers2072-66942022-04-01148193010.3390/cancers14081930CD47-SIRPα Checkpoint Disruption in Metastases Requires Tumor-Targeting Antibody for Molecular and Engineered Macrophage TherapiesJason C. Andrechak0Lawrence J. Dooling1Michael P. Tobin2William Zhang3Brandon H. Hayes4Justine Y. Lee5Xiaoling Jin6Jerome Irianto7Dennis E. Discher8Biophysical Engineering Labs, University of Pennsylvania, Philadelphia, PA 19104, USABiophysical Engineering Labs, University of Pennsylvania, Philadelphia, PA 19104, USABiophysical Engineering Labs, University of Pennsylvania, Philadelphia, PA 19104, USABiophysical Engineering Labs, University of Pennsylvania, Philadelphia, PA 19104, USABiophysical Engineering Labs, University of Pennsylvania, Philadelphia, PA 19104, USABiophysical Engineering Labs, University of Pennsylvania, Philadelphia, PA 19104, USABiophysical Engineering Labs, University of Pennsylvania, Philadelphia, PA 19104, USABiophysical Engineering Labs, University of Pennsylvania, Philadelphia, PA 19104, USABiophysical Engineering Labs, University of Pennsylvania, Philadelphia, PA 19104, USAThe macrophage checkpoint interaction CD47-SIRPα is an emerging target for cancer therapy, but clinical trials of monoclonal anti-CD47 show efficacy only in liquid tumors when combined with tumor-opsonizing IgG. Here, in challenging metastatic solid tumors, CD47 deletion shows no effect on tumor growth unless combined with otherwise ineffective tumor-opsonization, and we likewise show wild-type metastases are suppressed by SIRPα-blocked macrophages plus tumor-opsonization. Lung tumor nodules of syngeneic B16F10 melanoma cells with CD47 deletion show opsonization drives macrophage phagocytosis of B16F10s, consistent with growth versus phagocytosis calculus for exponential suppression of cancer. Wild-type CD47 levels on metastases in lungs of immunocompetent mice and on human metastases in livers of immunodeficient mice show that systemic injection of antibody-engineered macrophages also suppresses growth. Such in vivo functionality can be modulated by particle pre-loading of the macrophages. Thus, even though CD47-SIRPα disruption and tumor-opsonizing IgG are separately ineffective against established metastatic solid tumors, their combination in molecular and cellular therapies prolongs survival.https://www.mdpi.com/2072-6694/14/8/1930macrophage checkpointCD47metastasismelanomacell therapySIRPα |
| spellingShingle | Jason C. Andrechak Lawrence J. Dooling Michael P. Tobin William Zhang Brandon H. Hayes Justine Y. Lee Xiaoling Jin Jerome Irianto Dennis E. Discher CD47-SIRPα Checkpoint Disruption in Metastases Requires Tumor-Targeting Antibody for Molecular and Engineered Macrophage Therapies Cancers macrophage checkpoint CD47 metastasis melanoma cell therapy SIRPα |
| title | CD47-SIRPα Checkpoint Disruption in Metastases Requires Tumor-Targeting Antibody for Molecular and Engineered Macrophage Therapies |
| title_full | CD47-SIRPα Checkpoint Disruption in Metastases Requires Tumor-Targeting Antibody for Molecular and Engineered Macrophage Therapies |
| title_fullStr | CD47-SIRPα Checkpoint Disruption in Metastases Requires Tumor-Targeting Antibody for Molecular and Engineered Macrophage Therapies |
| title_full_unstemmed | CD47-SIRPα Checkpoint Disruption in Metastases Requires Tumor-Targeting Antibody for Molecular and Engineered Macrophage Therapies |
| title_short | CD47-SIRPα Checkpoint Disruption in Metastases Requires Tumor-Targeting Antibody for Molecular and Engineered Macrophage Therapies |
| title_sort | cd47 sirpα checkpoint disruption in metastases requires tumor targeting antibody for molecular and engineered macrophage therapies |
| topic | macrophage checkpoint CD47 metastasis melanoma cell therapy SIRPα |
| url | https://www.mdpi.com/2072-6694/14/8/1930 |
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