Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma
Open accessAbstract
Osteosarcoma is the most frequent primary bone tumor with poor prognosis. Through RNA-sequencing of 100,987 individual cells from 7 primary, 2 recurrent, and 2 lung metastatic osteosarcoma lesions, 11 major cell clusters are identified based on unbiased clustering of gene expression profiles and canonical markers. The transcriptomic properties, regulators and dynamics of osteosarcoma malignant cells together with their tumor microenvironment particularly stromal and immune cells are characterized. The transdifferentiation of malignant osteoblastic cells from malignant chondroblastic cells is revealed by analyses of inferred copy-number variation and trajectory. A proinflammatory FABP4 + macrophages infiltration is noticed in lung metastatic osteosarcoma lesions. Lower osteoclasts infiltration is observed in chondroblastic, recurrent and lung metastatic osteosarcoma lesions compared to primary osteoblastic osteosarcoma lesions. Importantly, TIGIT blockade enhances the cytotoxicity effects of the primary CD3 + T cells with high proportion of TIGIT + cells against osteosarcoma. These results present a single-cell atlas, explore intratumor heterogeneity, and provide potential therapeutic targets for osteosarcoma.
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Blocking TIGIT signaling significantly enhances the cytotoxicity of CD3+ T cells with high TIGIT expression against osteosarcoma cells.
“Blocking TIGIT signaling can significantly enhance the cytotoxicity effects of CD3+ T cells with high expression of TIGIT against osteosarcoma cells, indicating potential therapeutic value of targeted TIGIT therapy for osteosarcoma [4].”
From Advances on immunotherapy for osteosarcoma (2024) · cites this paper as [4]
The Results (Heterogeneity of the TILs) report that TIGIT blockade significantly increased osteosarcoma-cell death in co-cultures with CD3+ T cells from patients BC3 and BC16, and the Discussion describes potential therapeutic value. Those patients had relatively high infiltration of TIGIT-positive CD3+ T cells in their tumors; the passage does not establish that the peripheral-blood CD3+ T cells used in the assay themselves had high TIGIT expression. (LLM, conf=0.82)
Experimental — accuracy not yet measuredTIGIT is highly expressed by CD8+ T, CD4+ T, Treg and NKT cells in osteosarcoma lesions.
“And the immunoreceptor inhibitory checkpoint marker TIGIT was highly expressed by the CD8+ T, CD4+ T, Treg and NKT cells in osteosarcoma lesions.”
From Advances on immunotherapy for osteosarcoma (2024) · cites this paper as [4]
Targeted TIGIT therapy has potential therapeutic value for osteosarcoma.
“indicating potential therapeutic value of targeted TIGIT therapy for osteosarcoma [4]”
From Advances on immunotherapy for osteosarcoma (2024) · cites this paper as [4]
The seed and soil phenomenon in osteosarcoma is driven by a microenvironment that modulates osteosarcoma cell behaviour and facilitates proliferation, quiescence, invasion, migration and drug resistance, and contributes to intrinsic heterogeneity.
“This seed and soil phenomenon is driven by a microenvironment that modulates osteosarcoma cell behaviour and facilitates proliferation, quiescence, invasion, migration, and drug resistance 15,51,52,53 and contributes to their intrinsic heterogeneity 54,55 .”
From Osteosarcoma (2022) · cites this paper as [54]
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Self-citation
- Authors
- Zhou, Y., Yang, D., Yang, Q., Lv, X., Huang, W., Zhou, Z., Wang, Y., Zhang, Z., Yuan, T., Ding, X., Tang, L., Zhang, J., Yin, J., Huang, Y., Yu, W., Wang, Y., Zhou, C., Su, Y., He, A., Sun, Y., Shen, Z., Qian, B., Meng, W., Fei, J., Yao, Y., Pan, X., Chen, P., & Hu, H.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Third Affiliated Hospital of Nanchang University (CN)
- Second Military Medical University (CN)
- Southern Medical University (CN)
- Jinan University (CN)
- Key Laboratory of Guangdong Province (CN)
- Corresponding author
- Yao, Yang
- Pan, Xinghua
- Chen, Peizhan
- Hu, Haiyan
- ORCID
- Venue
- Nature Communications
- Published
- 2020-12-10
- Volume
- 11
- Issue
- 1
- Pages
- 6322-6322
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7730477
- OpenAlex
- W3110998212
- Cited by
- 672
- References
- 96
- Citations by year
- 2026: 106 · 2025: 136 · 2024: 152 · 2023: 139 · 2022: 96 · 2021: 41 · 2020: 2
- FWCI
- 40.35
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-04-30)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (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
- National Natural Science Foundation of China (81372873, 8187215, 81503396, 81770173)
- Please indicate the funder(s) of the research described in this manuscript, and the associated grant reference numbers
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
- Keywords
- osteosarcoma, intratumoral heterogeneity, tumor microenvironment, immunosuppression, single-cell transcriptomics, cell of origin, osteoblastic osteosarcoma, chondroblastic osteosarcoma, transdifferentiation, copy number variation, macrophage infiltration, FABP4, osteoclasts, lung metastasis, recurrent osteosarcoma, TIGIT, CD3+ T cells
- MeSH terms
- Cancer-Associated Fibroblasts, Adolescent, Adult, Cell Aggregation, Child, Clone Cells, Dendritic Cells, Female, Humans, Immunosuppression Therapy, Macrophages, Male, Neoplasm Staging, Osteoclasts, RNA, Neoplasm, Osteosarcoma, Lymphocytes, Tumor-Infiltrating, Stromal Cells, Genetic Heterogeneity, Myeloid Cells, Young Adult, DNA Copy Number Variations, Single-Cell Analysis, Tumor Microenvironment, Transcriptome, Mesenchymal Stem Cells
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