Immuno-genomic landscape of osteosarcoma
Open accessAbstract
Limited clinical activity has been seen in osteosarcoma (OS) patients treated with immune checkpoint inhibitors (ICI). To gain insights into the immunogenic potential of these tumors, we conducted whole genome, RNA, and T-cell receptor sequencing, immunohistochemistry and reverse phase protein array profiling (RPPA) on OS specimens from 48 pediatric and adult patients with primary, relapsed, and metastatic OS. Median immune infiltrate level was lower than in other tumor types where ICI are effective, with concomitant low T-cell receptor clonalities. Neoantigen expression in OS was lacking and significantly associated with high levels of nonsense-mediated decay (NMD). Samples with low immune infiltrate had higher number of deleted genes while those with high immune infiltrate expressed higher levels of adaptive resistance pathways. PARP2 expression levels were significantly negatively associated with the immune infiltrate. Together, these data reveal multiple immunosuppressive features of OS and suggest immunotherapeutic opportunities in OS patients.
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A recent comprehensive characterization of the immuno-genomic landscape of osteosarcoma suggests that the majority of osteosarcomas are "cold" tumors, with low levels of immune cell infiltration, low-to-moderate tumor mutation burden and lack of neoantigen expression.
“A recent and comprehensive characterization of the immuno-genomic landscape of osteosarcoma suggests that the majority of osteosarcomas are “cold” tumors, with low levels of immune cell infiltration, low-to-moderate tumor mutation burden and lack of neoantigen expression [24].”
From Pembrolizumab in advanced osteosarcoma: results of a single-arm, open-label, phase 2 trial (2021) · cites this paper as [24]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredDue to high heterogeneity of somatic mutations in osteosarcoma, a tumor-agnostic MRD panel would compromise sensitivity.
“However, due to the high heterogeneity of somatic mutations in osteosarcoma,14,15 the use of a tumor-agnostic MRD panel would compromise sensitivity, leading to reduced sequencing depth and overlooking unique somatic variants.”
From Tumor-informed deep sequencing of ctDNA detects minimal residual disease and predicts relapse in osteosarcoma (2024) · cites this paper as [15]
There are likely multiple immune-suppressive mechanisms in play in osteosarcoma.
“Besides, there are likely multiple immune-suppressive mechanisms in play in osteosarcoma [75].”
From Advances on immunotherapy for osteosarcoma (2024) · cites this paper as [75]
Osteosarcoma tumours often show signs of whole-genome duplication, which probably occurs in response to stresses imposed by pervasive copy number losses.
“Osteosarcoma tumours often show signs of whole-genome duplication, which probably occurs in response to stresses imposed by pervasive copy number losses 36 .”
From Osteosarcoma (2022) · cites this paper as [36]
Deletion of ATRX seems to activate alternative lengthening of telomeres and is associated with decreased survival in osteosarcoma.
“deletion of ATRX, which seems to activate alternative lengthening of telomeres and is associated with decreased survival 36,43 .”
From Osteosarcoma (2022) · cites this paper as [36]
The single most frequently altered gene in osteosarcoma is TP53, which is lost in more than 90% of tumours, with most losses through intron 1 rearrangements or deletions rather than point mutations.
“The single most frequently altered gene is the tumour suppressor TP53, which is lost in >90% of osteosarcoma tumours, with the majority lost through intron 1 rearrangements or deletions rather than through point mutations 33,36,38 .”
From Osteosarcoma (2022) · cites this paper as [36]
Large-scale sequencing has identified only moderate levels of point mutations in osteosarcoma, with few recurrently mutated genes.
“large-scale sequencing has identified only moderate levels of point mutations with few recurrently mutated genes 33,34,36,38 .”
From Osteosarcoma (2022) · cites this paper as [36]
Older patients with osteosarcoma have a profile that is more associated with response to immune-checkpoint inhibitors.
“Even in the context of osteosarcoma, older patients have a profile that is more associated with response to ICIs 36 .”
From Osteosarcoma (2022) · cites this paper as [36]
Despite being known as one of the most genomically complex paediatric malignancies, many alterations in osteosarcoma are translocation events that silence genes rather than create neoantigens.
“Despite being known as one of the most genomically complex paediatric malignancies, many of the alterations that occur in osteosarcoma are translocation events that silence genes rather than create neoantigens 36 .”
From Osteosarcoma (2022) · cites this paper as [36]
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- Authors
- Wu, C.-C., Beird, H. C., Andrew Livingston, J., Advani, S., Mitra, A., Cao, S., Reuben, A., Ingram, D., Wang, W.-L., Ju, Z., Hong Leung, C., Lin, H., Zheng, Y., Roszik, J., Wang, W., Patel, S., Benjamin, R. S., Somaiah, N., Conley, A. P., Mills, G. B., Hwu, P., Gorlick, R., Lazar, A., Daw, N. C., Lewis, V., & Futreal, P. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Futreal, P. Andrew
- ORCID
- Wu, Chia-Chin
- Beird, Hannah C.
- Andrew Livingston, J.
- Advani, Shailesh
- Mitra, Akash
- Cao, Shaolong
- Reuben, Alexandre
- Ingram, Davis
- Wang, Wei-Lien
- Ju, Zhenlin
- Lin, Heather
- Zheng, Youyun
- Roszik, Jason
- Wang, Wenyi
- Patel, Shreyaskumar
- Benjamin, Robert S.
- Somaiah, Neeta
- Conley, Anthony P.
- Mills, Gordon B.
- Hwu, Patrick
- Gorlick, Richard
- Lazar, Alexander
- Daw, Najat C.
- Lewis, Valerae
- Futreal, P. Andrew
- Venue
- Nature Communications
- Published
- 2020-02-21
- Volume
- 11
- Issue
- 1
- Pages
- 1008-1008
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7035358
- OpenAlex
- W3006860236
- Cited by
- 251
- References
- 60
- Citations by year
- 2026: 27 · 2025: 39 · 2024: 44 · 2023: 30 · 2022: 44 · 2021: 48 · 2020: 19
- FWCI
- 19.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- A Shelter for Cancer Families
- Cancer Prevention and Research Institute of Texas (R120501)
- QuadW Foundation
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
- Keywords
- osteosarcoma, tumor immune microenvironment, immune checkpoint inhibitors, T-cell receptor clonality, neoantigens, nonsense-mediated mRNA decay, immune cell infiltration, PARP2, immunosuppression, pediatric osteosarcoma, immunotherapy
- MeSH terms
- Whole Genome Sequencing, RNA-Seq, Adolescent, Adult, Aged, Aged, 80 and over, Bone Neoplasms, Child, Child, Preschool, Female, Humans, Male, Middle Aged, Mutation, Receptors, Antigen, T-Cell, Osteosarcoma, Cohort Studies, Immunogenetic Phenomena, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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