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CD47-SIRPα Checkpoint Disruption in Metastases Requires Tumor-Targeting Antibody for Molecular and Engineered
Jason C Andrechak1,2, Lawrence J Dooling1, Michael P Tobin1,2
1Biophysical Engineering Labs, University of Pennsylvania, Philadelphia, PA 19104, USA.
Abstract:
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.
Insights
Combining CD47-SIRPα disruption with tumor opsonization effectively suppresses established metastatic solid tumors. This dual approach enhances macrophage phagocytosis, prolonging survival in preclinical models.
Area of Science:
- Immunology
- Oncology
- Cancer Therapy
Background:
- The CD47-SIRPα axis is a key macrophage checkpoint and a target for cancer immunotherapy.
- Anti-CD47 therapies show limited efficacy in solid tumors, often requiring combination with tumor-opsonizing antibodies.
Purpose of the Study:
- To investigate the efficacy of combined CD47 blockade and tumor opsonization in established metastatic solid tumors.
- To explore the role of macrophages in mediating tumor suppression in this context.
Main Methods:
- Utilized syngeneic B16F10 melanoma models and human metastases in immunodeficient mice.
- Administered CD47 deletion, SIRPα blockade, and tumor opsonization, both individually and in combination.
- Investigated macrophage phagocytosis and tumor growth dynamics.
- Assessed the impact of particle pre-loading on engineered macrophage functionality.
Main Results:
- CD47 deletion alone did not inhibit tumor growth in solid metastases.
- Combination therapy (CD47 blockade + tumor opsonization) suppressed tumor growth.
- SIRPα-blocked macrophages plus tumor opsonization effectively suppressed wild-type metastases.
- Engineered macrophages, systemically injected, suppressed tumor growth in vivo.
- Macrophage functionality could be modulated by particle pre-loading.
Conclusions:
- CD47-SIRPα disruption and tumor opsonization are synergistic in treating established metastatic solid tumors.
- Combined molecular and cellular therapies targeting this axis offer a promising strategy to prolong survival.
- Macrophage-mediated phagocytosis is crucial for tumor suppression in this combined therapy approach.
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