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Updated: May 29, 2025
Intratibial Osteosarcoma Cell Injection to Generate Orthotopic Osteosarcoma and Lung Metastasis Mouse Models
Published on: October 28, 2021
Spatial profiling identifies regionally distinct microenvironments and targetable immunosuppressive mechanisms in
Jason Eigenbrood1,2,3, Nathan Wong4,5,3, Paul Mallory6
1Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Abstract:
Osteosarcoma is the most common malignant bone tumor in young patients and remains a significant clinical challenge, particularly in the context of metastatic disease. Despite extensive documentation of genomic alterations in osteosarcoma, studies detailing the immunosuppressive mechanisms within the metastatic osteosarcoma microenvironment are lacking. Our objective was to characterize the spatial transcriptional landscape of metastatic osteosarcoma to reveal these immunosuppressive mechanisms and identify promising therapeutic targets. Here, we performed spatial transcriptional profiling on a cohort of osteosarcoma pulmonary metastases from pediatric patients. We reveal a conserved spatial gene expression pattern resembling a foreign body granuloma, characterized by peripheral inflammatory signaling, fibrocollagenous encapsulation, lymphocyte exclusion, and peritumoral macrophage accumulation. We also show that the intratumoral microenvironment of these lesions lack inflammatory signaling. Additionally, we identified CXCR4 as an actionable immunomodulatory target that bridges both the intratumoral and extratumoral microenvironments and highlights the spatial heterogeneity and complexity of this pathway. Collectively, this study reveals that metastatic osteosarcoma specimens are comprised of multiple regionally distinct immunosuppressive microenvironments.
Insights
Metastatic osteosarcoma exhibits distinct immunosuppressive microenvironments, resembling a foreign body granuloma. This spatial organization, particularly lymphocyte exclusion, offers new therapeutic targets like CXCR4 for osteosarcoma treatment.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Osteosarcoma is a prevalent bone cancer in young patients, with metastatic disease posing a major challenge.
- Genomic studies are extensive, but the immunosuppressive mechanisms in metastatic osteosarcoma microenvironments are poorly understood.
Purpose of the Study:
- To spatially map the transcriptional landscape of pulmonary osteosarcoma metastases.
- To identify immunosuppressive mechanisms and potential therapeutic targets within these microenvironments.
Main Methods:
- Spatial transcriptional profiling was conducted on pediatric osteosarcoma pulmonary metastases.
- Gene expression patterns were analyzed to understand microenvironmental characteristics.
Main Results:
- A conserved spatial gene expression pattern, similar to a foreign body granuloma, was observed.
- This pattern includes peripheral inflammation, encapsulation, lymphocyte exclusion, and peritumoral macrophage accumulation.
- Intratumoral regions lacked inflammatory signaling, while CXCR4 emerged as a key immunomodulatory target.
Conclusions:
- Metastatic osteosarcoma contains multiple, distinct immunosuppressive microenvironments.
- Understanding this spatial heterogeneity is crucial for developing effective osteosarcoma therapies.
- CXCR4 represents a promising target for modulating the immune response in osteosarcoma.
