Inhibiting autophagy enhances idarubicin chemosensitivity and induces immune escape in FAT1-low-expressing AML cells.

Objective: Both Autophagy and FAT atypical cadherin 1 (FAT1) regulates the chemosensitivity and immune escape of tumour cells. Our previous paper showed that FAT1 decreased acute myeloid leukemia (AML) autophagy by inhibiting the TGFβ-Smad2/3 pathway. This study builds upon our previous paper and aims to explore whether FAT1-inhibited autophagy is involved in regulating chemosensitivity and immune escape in AML.

Methods: We validated the inhibitory effect of FAT1 on AML autophagy through western blot, qPCR, and luciferase reporter assays. In addition, we explored the effect of FAT1-inhibited autophagy on idarubicin (IDA) sensitivity and AML immune escape through caspase-3 activity analysis, trypan blue exclusion assays, and flow cytometry.

Results: We demonstrated for the first time that the autophagy inhibitor chloroquine (CQ) enhances the cytotoxic effect of IDA on FAT1-low-expressing (FAT1-L) AML cells. We also found that CQ weakened CD8 T cell infiltration in FAT1-L AML cells. Further research revealed that CQ upregulated PD-L1 protein levels by decreasing its autophagic degradation and that the PD-L1 inhibitor atezolizumab reversed the decrease in CD8 T cell infiltration caused by CQ in FAT1-L AML cells. In addition, we found that FAT1 decreased autophagy related 10 (ATG10) transcription, leading to decreased AML autophagy.

Conclusions: These results revealed that in FAT1-L AML cells, inhibiting autophagy by CQ enhances the cytotoxic effect of IDA, but leads to immune escape, resulting in AML recurrence. Our study supports the use of a combination of autophagy and PD-L1 inhibitors with IDA to increase the cytotoxic effect of IDA while inhibiting AML recurrence.