Targeted therapies prime oncogene-driven lung cancers for macrophage-mediated destruction

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Macrophage immune checkpoint inhibitors like anti-CD47 antibodies are promising for cancer treatment.
• Optimal combination strategies for these therapies are still under investigation.
• Combining therapies may enhance efficacy in solid and hematologic malignancies.

Approach:

• Developed a novel screening platform to identify drugs enhancing cancer cell vulnerability to macrophages.
• Investigated the synergistic potential of genotype-directed therapies and anti-CD47 antibodies in lung cancer.
• Validated findings in vitro and in vivo, assessing phagocytosis, tumor response, and molecular mechanisms.

Key Points:

• Therapeutic synergy was identified between genotype-directed therapies and anti-CD47 antibodies.
• The combination therapy promoted robust phagocytosis and eliminated persister cells in vitro.
• Maximized anti-tumor responses were observed in vivo across various lung cancer genetic alterations (EGFR, ALK, KRAS).
• Downregulation of β2-microglobulin and CD73 were identified as mechanisms of enhanced macrophage attack sensitivity.

Conclusions:

• Dual inhibition of the RTK/MAPK pathway and the CD47/SIRPa axis represents a promising immunotherapeutic strategy.
• This combination approach is effective against lung cancers with diverse driver mutations.
• The study provides a strong rationale for clinical trials combining these therapies in lung cancer patients.