RNA methylation of CD47 mediates tumor immunosuppression in EGFR-TKI resistant NSCLC.

Abstract

Background: Although immune checkpoint inhibitors (ICIs) have been successfully utilized in patients with non-small cell lung cancer (NSCLC), EGFR-mutated patients didn't benefit from ICIs. The underlying mechanisms for the poor efficacy of this subgroup remain unclear.

Methods: CD8⁺T cells cytotoxicity, DCs phagocytosis and immunofluorescence assay were applied to examine the immunosuppressive microenvironment of NSCLC. m⁶A RNA immunoprecipitation, luciferase assay and immunohistochemistry were used to explore the relationship between CD47 and ALKBH5 in EGFR-TKI resistant NSCLC. Autochthonous EGFR-driven lung tumor mouse model and PDXs were performed to explore the therapeutic potential of CD47 antibody and EGFR-TKI combination.

Results: We found that EGFR-TKI resistance promoted a more immunosuppressive tumor microenvironment and inhibited anti-tumor functions of CD8⁺ T cells. Mechanistically, the m⁶A eraser ALKBH5 was inhibited in EGFR-TKI resistant NSCLC, which subsequently upregulates CD47 by catalyzing m⁶A demethylation and causes immunosuppression. Combined treatment with EGFR-TKI and inhibitors of CD47 enhances antitumor immunity and EGFR-TKI efficacy in vivo.

Conclusions: Collectively, our findings reveal the possible underlying mechanism for poor immune response of ICIs in EGFR-TKI resistant NSCLC and provide preclinical evidence that targeted therapy combined with innate immune checkpoint blockade may provide synergistic effects in NSCLC treatment.