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

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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. 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. 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. 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.