Targeting ALDH1A1 with Nanoparticle-Based Immunotherapy on Kidney PD-L1 Synergistically Delays Cyst Growth
- Genetic Diseases: Cystic - Therapeutic Investigations and Prognosis
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
- Cheng, Shasha, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
- Li, Xiaoyan, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
- Zhou, Xia, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
- Calvet, James P., Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas, Missouri, United States
- Li, Xiaogang, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
ALDH1A1 is responsible for oxidation of acetaldehyde in mammals, which is upregulated in various cancers to drive cancer growth. ALDH1A1 is associated with tumor immunity by regulating the ratio of effector T cells to Treg cells within tumor tissues. However, the role of ALDH1A1 and its relationship with PD-L1 as well as the PD-L1 mediated immune response in ADPKD remains elusive.
To investigate the role of ALDH1A1 and its relationship with PD-L1 in ADPKD, we treated Pkd1 mutant mouse models with the ALDH1A1 inhibitor DSF either alone or together with nanoparticles carrying PD-L1 antibody and evaluated their effect on cyst growth, immune response and fibrosis as well as on specific PKD associated signaling pathways by immunostaining, Western blot, qRT-PCR and flow cytometry analysis. To increase kidney specificity, nanoparticles were conjugated with PD-L1 and kidney specific cadherin-16 (CDH16) antibodies.
ALDH1A1 was upregulated in cyst lining epithelial cells in Pkd1 mutant kidneys. Targeting ALDH1A1 with its specific inhibitor DSF decreased cyst growth as seen by the decrease of cystic index, KW/BW ratio and BUN levels in Pkd1RC/RC kidneys as well as cyst lining epithelial cell proliferation by the decrease of the activation of AURKA, AKT, S6 and STAT3. In addition, treatment with DSF decreased the expression of PD-L1 and activated the immune response characterized by the increase of CD8+ T cells as examined by flow cytometry analysis, and decrease the recruitment of macrophages. Our CHIP assay indicated that ALDH1A1 bound with the promoter of PD-L1 to regulate its transcription. Treatment with DSF induced cystic renal epithelial cell death which should be mediated by the downregulation of PD-L1 and the activation of CD8+ T cells in Pkd1RC/RC kidneys. ALDH1A1 can also bind with the promoter of CCL2 to regulate its transcription, which is responsible for the recruitment of macrophages. Treatment with DSF and mesoporous silica nanoparticles (MSN) conjugated with PD-L1 and CDH16 antibodies has a synergistic effect on cyst growth.
ALDH1A1 is a novel transcription factor which binds the promoters of specific genes, such as PD-L1, CCL2 and fibrotic genes. Targeting ALDH1A1 with its inhibitor either alone or in combination with nanoparticle-mediated PD-L1 antibody is a novel therapeutic strategy for ADPKD.