Immunosuppressive Tumor Microenvironment of Osteosarcoma
<b>Background/Objectives:</b> Osteosarcoma is the most common malignant bone tumor in children, characterized by a high degree of genomic instability, resulting in copy number alterations and genomic rearrangements without disease-defining recurrent mutations. Clinical trials based on molecular characterization have failed to find new effective therapies or improve outcomes over the last 40 years. <b>Methods:</b> To better understand the immune microenvironment of osteosarcoma, we performed single-cell RNA sequencing on six tumor biopsy samples, combined with a previously published cohort of six samples. Additional osteosarcoma samples were profiled using spatial transcriptomics for the validation of discovered subtypes and to add spatial context. <b>Results:</b> Analysis revealed immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), regulatory and exhausted T cells, and LAMP3+ dendritic cells. <b>Conclusions:</b> Using cell-cell communication modeling, we identified robust interactions between MDSCs and other cells, leading to NF-κB upregulation and an immunosuppressive microenvironment, as well as interactions involving regulatory T cells and osteosarcoma cells that promoted tumor progression and a proangiogenic niche.
Authors
- Paul Robson (ORCID: https://orcid.org/0000-0002-0191-3958)
- Aaron Taylor (ORCID: https://orcid.org/0000-0002-2544-5888)
- Stephen T.C. Wong (ORCID: https://orcid.org/0000-0001-9188-6502)
- Jianting Sheng (ORCID: https://orcid.org/0000-0003-3532-3259)
- Nathaniel Jillette (ORCID: https://orcid.org/0000-0003-3328-4401)
- Michael S. Isakoff (ORCID: https://orcid.org/0000-0003-4790-9919)
- Elise T. Courtois (ORCID: https://orcid.org/0000-0002-8749-2719)
- Alini Trujillo-Paolillo (ORCID: https://orcid.org/0000-0001-6609-196X)
- Qian Wu (ORCID: https://orcid.org/0000-0001-7646-8329)
- Andrew Goodspeed (ORCID: https://orcid.org/0000-0001-7055-7128)
- Joshy George (ORCID: https://orcid.org/0000-0001-8510-8229)
- Masanori Hayashi (ORCID: https://orcid.org/0000-0002-9508-0159)
- Adam D. Lindsay (ORCID: https://orcid.org/0000-0002-4188-9681)
- Ching C. Lau (ORCID: https://orcid.org/0000-0001-9173-8366)
- Fabiola Balarezo
- Diane Luo
- Avery Bodlak (ORCID: https://orcid.org/0000-0001-9207-1532)
- William F. Flynn (ORCID: https://orcid.org/0000-0001-6533-0340)
- Ju Young Ahn (ORCID: https://orcid.org/0000-0002-0946-4157)
- Antônio Sérgio Petrilli (ORCID: https://orcid.org/0000-0002-5392-0535)
- Bang H. Hoang (ORCID: https://orcid.org/0000-0002-2950-3221)
- Sílvia Regina Caminada de Toledo (ORCID: https://orcid.org/0000-0001-7808-3393)
- Parveen Kumar (ORCID: https://orcid.org/0000-0003-2739-273X)
- Jessica Grassmann (ORCID: https://orcid.org/0000-0001-9076-452X)
- Jeffrey M. Harder (ORCID: https://orcid.org/0000-0003-3832-3553)
- Alissa M. Dzis (ORCID: https://orcid.org/0009-0008-5898-5507)
- Patrick Kwok Shing Ng
- Yuliang Cao
Institutions
- Houston Methodist (US)
- Hartford Hospital (US)
- Montefiore Medical Center (US)
- University of Connecticut (US)
- Cornell University (US)
- Support group for adolescents and children with cancer (BR)
- Children's Hospital Colorado (US)
- Connecticut Children's Medical Center (US)
- Jackson Laboratory (US)
- University of Colorado Anschutz Medical Campus (US)
- Texas A&M University (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- Cancers
- Published
- 2025-06-24
- DOI
- https://doi.org/10.3390/cancers17132117
- Citations
- 10
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 10.45
Funders
- John S. Dunn Foundation
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- National Institutes of Health
- Cancer Center, University of Colorado