Targeting HDAC6 improves anti-CD47 immunotherapy

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• CD47, an immune checkpoint, is overexpressed in cancer cells, inhibiting macrophage phagocytosis via SIRPα interaction.
• CD47 blockade shows promise in hematological cancers but has limited efficacy in solid tumors like melanoma.
• Histone deacetylase 6 inhibitors (HDAC6is) possess immunomodulatory properties, yet their role in the CD47/SIRPα axis is unclear.

Purpose of the Study:

• To investigate the role of HDAC6 in regulating the CD47/SIRPα axis and macrophage phagocytosis.
• To evaluate the therapeutic potential of HDAC6 inhibition in combination with CD47 blockade for melanoma treatment.

Main Methods:

• Utilized bone marrow-derived macrophages and cell lines to assess HDAC6is' effects on macrophage phenotype and phagocytosis.
• Investigated CD47/SIRPα axis modulation and phagocytosis using murine and human melanoma cells and macrophages.
• Conducted in vivo studies with melanoma mouse models to evaluate the antitumor activity of Nexturastat A combined with anti-CD47 or anti-SIRPα antibodies.

Main Results:

• HDAC6 inhibition promoted antitumoral M1 macrophage polarization and reduced protumoral M2 phenotype.
• HDAC6 inhibition decreased SIRPα expression, increased pro-phagocytic signals, and downregulated CD47 on melanoma cells.
• Combined HDAC6 inhibition and anti-CD47 therapy enhanced macrophage phagocytosis and in vivo antitumor activity in melanoma models.

Conclusions:

• HDAC6 plays a critical role in regulating macrophage phagocytosis and innate immunity.
• HDAC6 inhibitors can potentiate CD47 immune checkpoint blockade strategies for cancer therapy.
• Combination therapy with HDAC6is and anti-CD47 antibodies demonstrates significant antitumor activity in melanoma.