Profiling targetable immune checkpoints in osteosarcoma.

Area of Science:

• Oncology
• Genomics
• Immunology

Background:

• Osteosarcomas are aggressive bone tumors with limited therapeutic progress.
• Osteosarcoma genomes exhibit significant instability, including copy number alterations and structural aberrations.

Purpose of the Study:

• To investigate the impact of copy number alterations on targetable immune checkpoints (CD274/PD-L1, PDCD1LG2/PD-L2, CD276/B7-H3, IDO1) in osteosarcoma.
• To explore the expression profiles and clinical significance of these immune checkpoints in osteosarcoma.

Main Methods:

• Analysis of genomic copy number alterations in 215 osteosarcoma samples.
• RNA sequencing of two independent osteosarcoma cohorts.
• Protein expression analysis and correlation with patient survival.
• In vitro studies using osteosarcoma cell lines and an IDO1 inhibitor (epacadostat).

Main Results:

• PD-L1/PD-L2, B7-H3, and IDO1 gains occurred in approximately 24% of osteosarcoma samples.
• B7-H3 demonstrated the highest expression among the investigated immune checkpoints.
• Increased B7-H3 and IDO1 protein expression were significantly associated with inferior patient survival.
• IDO1 was preferentially expressed in pediatric solid tumors and its inhibition by epacadostat was confirmed in cell lines.

Conclusions:

• Genomic alterations in immune checkpoints are prevalent in osteosarcoma.
• B7-H3 and IDO1 represent potential therapeutic targets for a subset of osteosarcoma patients.
• These findings highlight a potential avenue for targeted immunotherapeutic interventions in osteosarcoma.