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CD47-SIRPα Blockade Sensitizes Head and Neck Squamous Cell Carcinoma to Cetuximab by Enhancing Macrophage Adhesion to
Bolei Li1,2, Yu Hao1,2, Hongzhi He1,2
1State Key Laboratory of Oral Disease & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Abstract:
Developing effective treatments for patients with head and neck squamous cell carcinoma (HNSCC) is a significant challenge. Cetuximab, a first-line targeted therapy for HNSCC, exhibits limited efficacy. Here, we used pooled CRISPR screening to find targets that can synergize with cetuximab and identified CD47 as the leading candidate. Rather than inhibiting cancer cell proliferation, CD47 inhibition promoted cetuximab-triggered antibody-dependent cellular phagocytosis (ADCP), thereby enhancing macrophage-mediated cancer cell removal. The combination of CD47-signal-regulatory protein α (SIRPα) blockade and cetuximab demonstrated strong anticancer activity in vivo. In addition to blocking the phagocytosis checkpoint, CD47-SIRPα inhibition upregulated CD11b/CD18 on the surface of macrophages, which accelerated intercellular adhesion between macrophages and cancer cells to enhance subsequent phagocytosis. Inhibition of the interaction between macrophage CD11b/CD18 and cancer cell intercellular adhesion molecule-1 (ICAM1) eliminated the intercellular adhesion and phagocytosis induced by CD47-SIRPα blockade. Thus, CD47-SIRPα blockade enhances ADCP through CD11b/CD18-ICAM1-mediated intercellular adhesion and sensitizes HNSCC to cetuximab. Significance: CD47-SIRPα blockade increases surface CD11b/CD18 on macrophages to enhance adhesion to cancer cells, resulting in robust synergistic phagocytosis in combination with cetuximab treatment in head and neck squamous cell carcinoma.
Insights
Combining CD47 blockade with cetuximab enhances cancer cell removal in head and neck squamous cell carcinoma (HNSCC). This strategy boosts macrophage-mediated phagocytosis, offering a promising new treatment approach for HNSCC patients.
Area of Science:
- Immunology
- Oncology
- Cancer Biology
Background:
- Head and neck squamous cell carcinoma (HNSCC) presents treatment challenges.
- Cetuximab, a targeted therapy for HNSCC, has limited efficacy.
- Identifying synergistic targets with cetuximab is crucial for improving HNSCC treatment.
Purpose of the Study:
- To identify targets that synergize with cetuximab in HNSCC.
- To investigate the mechanism by which CD47 inhibition enhances cetuximab efficacy.
- To evaluate the therapeutic potential of combining CD47 blockade with cetuximab.
Main Methods:
- Pooled CRISPR screening was employed to identify synergistic targets with cetuximab.
- The study assessed the impact of CD47 inhibition on antibody-dependent cellular phagocytosis (ADCP).
- In vivo studies evaluated the anticancer activity of combined CD47-signal-regulatory protein α (SIRPα) blockade and cetuximab.
Main Results:
- CD47 was identified as a key target that synergizes with cetuximab.
- CD47 inhibition enhanced cetuximab-triggered ADCP and macrophage-mediated cancer cell removal.
- The combination therapy demonstrated significant anticancer activity in vivo.
- CD47-SIRPα blockade upregulated macrophage CD11b/CD18, promoting adhesion to cancer cells via ICAM1, thereby enhancing phagocytosis.
Conclusions:
- CD47-SIRPα blockade synergizes with cetuximab to enhance ADCP in HNSCC.
- The combination therapy improves macrophage-mediated cancer cell clearance through CD11b/CD18-ICAM1 interactions.
- This approach offers a novel strategy to sensitize HNSCC to cetuximab treatment.
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