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Profiling targetable immune checkpoints in osteosarcoma

Troy A McEachron1,2,3, Timothy J Triche2,4, Laurie Sorenson1

  • 1Department of Translational Genomics.

Oncoimmunology
|December 8, 2018
PubMed

Insights

Osteosarcoma tumors show genomic instability impacting immune checkpoints like PD-L1, B7-H3, and IDO1. Increased B7-H3 and IDO1 expression correlates with poorer survival, suggesting potential immunotherapeutic targets.

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.
Keywords:
B7-H3CD276IDO1OsteosarcomaPD-L1PD-L2checkpoint

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