ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Osteosarcoma chemoresistance is often mediated by ABCB1 (ATP Binding Cassette transporter B1) efflux of doxorubicin.
• ABCA1 (ATP Binding Cassette transporter A1) effluxes IPP, activating anti-tumor Vγ9Vδ2 T-cells, offering a potential therapeutic avenue.
• The interplay between ABCB1, ABCA1, and immune response in osteosarcoma chemoresistance requires further investigation.

Purpose of the Study:

• To investigate the regulation of ABCA1 and ABCB1 in osteosarcoma.
• To determine if enhancing ABCA1-mediated Vγ9Vδ2 T-cell activation can overcome chemoresistance in ABCB1-expressing osteosarcoma.
• To explore novel therapeutic strategies targeting chemo-immune-resistant osteosarcoma.

Main Methods:

• Utilized 2D and 3D cell cultures of doxorubicin-sensitive and resistant osteosarcoma cell lines (U-2OS, Saos-2).
• Analyzed protein and gene expression of ABCA1 and ABCB1.
• Investigated signaling pathways (Ras/Akt/mTOR, Ras/ERK1/2/HIF-1α) and their role in regulating ABCA1 and ABCB1.
• Tested the efficacy of zoledronic acid-loaded nanoparticles (NZ) in vitro and in humanized mouse models.

Main Results:

• Doxorubicin-resistant osteosarcoma cells and 3D cultures showed increased ABCB1, decreased ABCA1, reduced IPP efflux, and impaired Vγ9Vδ2 T-cell killing.
• The Ras/Akt/mTOR and Ras/ERK1/2/HIF-1α axes were identified as key regulators of ABCA1 and ABCB1, respectively.
• Targeting Ras farnesylation with NZ simultaneously inhibited these axes, restoring doxorubicin sensitivity and Vγ9Vδ2 T-cell activity.
• In vivo, NZ reduced tumor growth, increased necro-apoptosis, and enhanced ABCA1/ABCB1 ratio and T-cell infiltration.

Conclusions:

• The ABCB1^highABCA1^low phenotype signifies chemo-immune resistance in osteosarcoma.
• Targeting Ras farnesylation with zoledronic acid nanoparticles is a promising strategy to re-sensitize osteosarcoma to chemo-immunotherapy.
• Aminobisphosphonates represent a novel class of agents for overcoming drug resistance in osteosarcoma.