CD47-SIRPα Blockade Sensitizes Head and Neck Squamous Cell Carcinoma to Cetuximab by Enhancing Macrophage Adhesion to Cancer Cells

Jul 3, 2024Cancer research

Blocking CD47-SIRPα may help immune cells stick to head and neck cancer cells and improve response to cetuximab

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Abstract

CD47-SIRPα blockade is associated with enhanced antibody-dependent cellular phagocytosis in head and neck squamous cell carcinoma.

CD47 was identified as a leading candidate to synergize with cetuximab in treating head and neck squamous cell carcinoma.
Inhibition of CD47 promotes macrophage-mediated removal of cancer cells rather than directly stopping their growth.
The combination of CD47-SIRPα blockade and cetuximab showed strong anticancer activity in animal models.
This blockade increases the levels of CD11b/CD18 on macrophages, which improves their adhesion to cancer cells.
Blocking the interaction between macrophage CD11b/CD18 and cancer cell ICAM1 prevents phagocytosis enhanced by CD47-SIRPα blockade.

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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.

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