Aldehyde dehydrogenase 1 A1 regulates the transcription of PD-L1 and its targeting with disulfiram together with PD-L1 immunotherapy synergistically delays cyst growth in ADPKD.

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disease with no effective therapy to halt its progression. ALDH1A1, one of the aldehyde dehydrogenases, is the main ALDH1 isozyme known to oxidize 9-cis retinaldehyde into 9-cis retinoic acid, which can regulate the expression of the PKD1 gene. However, the role and mechanisms of ALDH1A1 in ADPKD remains elusive. To investigate this, Aldh1A1 was knocked out and ALDH1A1 inhibited with disulfiram (DSF) either alone or together with PD-L1 antibody in Pkd1 mutant mice. The effect of ALDH1A1 on cyst growth, immune response and PKD associated signaling pathways as well as the target genes of ALDH1A1 was determined by immunostaining, Western blot, qRT-PCR, flow cytometry, CUT-Tag analysis, and CHIP assay. ALDH1A1 was upregulated in ADPKD kidneys, leading to an activation of PKD associated signaling pathways, including AKT, S6, STAT3 and Rb. This was possibly mediated by AURKA, to increase cystic kidney epithelial cell proliferation. Knockout of Aldh1A1 delayed cyst growth in Pkd1 mutant kidneys. ALDH1A1 functions as a transcription factor to target diverse genes as examined by CUT-Tag analysis. Elevated ALDH1A1 regulated the transcription of Pd-l1 and Ccl2 to affect PD-L1 mediated immune surveillance and recruitment of macrophages, respectively. Inhibiting ALDH1A1 with DSF decreased cyst growth in aggressive (Pkd1^nl/nl) and mild (Pkd1^RC/RC) Pkd1 mouse models. Additionally, targeting ALDH1A1 in combination with PD-L1 antibody had a synergistic effect on delaying cyst growth in Pkd1 mutant mouse kidneys. Our study suggests that DSF is a promising agent for ADPKD treatment and highlights novel therapeutic strategies by the combination of chemotherapy with immunotherapy in ADPKD treatment.