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Cited by 155Cancer Immunotherapy and BiomarkersSarcoma Diagnosis and TreatmentImmunotherapy and Immune Responses

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PD-1 axis expression in musculoskeletal tumors and antitumor effect of nivolumab in osteosarcoma model of humanized mouse

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Zheng, Bingxin, Ren, Tingting, Huang, Yi, Sun, Kunkun, Wang, Shidong, Bao, Xing, Liu, Kuisheng, Guo, Wei·2018·Journal of Hematology & Oncology
DOI 10.1186/s13045-018-0560-1PMC PMC5801803
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Abstract

BACKGROUND: Immune checkpoint inhibitors have led to a breakthrough in solid tumor immunotherapy, but related studies on musculoskeletal tumors are few, especially for PD-L2. METHODS: We examined expression of three molecular effectors of the PD-1 axis in 234 patients with musculoskeletal tumors, including osteosarcoma, chondrosarcoma, synovial sarcoma, and giant cell tumor. Survival analyses and potential mechanisms were investigated in osteosarcoma per the Gene Expression Omnibus (GEO) and immunohistochemistry analyses. In vivo, humanized mice were used to evaluate the effect of nivolumab on osteosarcoma. RESULTS: PD-L1, PD-L2, and PD-1 expression levels were significantly different between the histologic types of the musculoskeletal tumors. For osteosarcoma, PD-L1 was negatively correlated with prognosis, while PD-1 had a negative correlation tendency with overall survival (OS). Meanwhile, PD-L2 had a positive correlation trend with OS. Nivolumab inhibited osteosarcoma metastasis in humanized mice by increasing CD4+ and CD8+ lymphocytes and the cytolytic activity of CD8 lymphocytes in the lung but did not affect primary osteosarcoma growth. CONCLUSION: We systematically detected the expression patterns of PD-L1, PD-L2, and PD-1 in musculoskeletal tumors for the first time and demonstrated the prognostic roles and underlying mechanisms of PD-1 axis in osteosarcoma. Furthermore, PD-1 blockade could effectively control osteosarcoma pulmonary metastasis in vivo. Therefore, the PD-1 axis may be a potential immunotherapeutic target for metastatic osteosarcoma.

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Figures

Fig. 1 IHC staining for PD-L1, PD-L2, and PD-1 expression in the TMA samples. PD-L1, PD-L2, and PD-1 exhibited a membranous expression accompanied by cytoplasmic expression. Representative images for every histological type are shown (The background image was magnified at × 50, while the insert image was magnified at × 400 in GCT. The other histological types were magnified at × 400)
Fig. 1 IHC staining for PD-L1, PD-L2, and PD-1 expression in the TMA samples. PD-L1, PD-L2, and PD-1 exhibited a membranous expression accompanied by cytoplasmic expression. Representative images for every histological type are shown (The background image was magnified at × 50, while the insert image was magnified at × 400 in GCT. The other histological types were magnified at × 400)CC BY · PubMed Central
Fig. 2 Survival analyses according to the PD-L1, PD-L2, and PD-1 expression levels in the GEO and IHC cohorts. a OS according to PD-L1, PD-L2, and PD-1 in the GEO cohort. b OS according to PD-L1, PD-L2, and PD-1 in the IHC cohort. c Subgroup survival analyses according to PD-L1 and PD-L2 expression in the IHC cohort. d Subgroup survival analyses according to PD-L1 and PD-1 expression in the IHC cohort. e Subgroup survival analyses according to PD-L2 and PD-1 expression in the IHC cohort
Fig. 2 Survival analyses according to the PD-L1, PD-L2, and PD-1 expression levels in the GEO and IHC cohorts. a OS according to PD-L1, PD-L2, and PD-1 in the GEO cohort. b OS according to PD-L1, PD-L2, and PD-1 in the IHC cohort. c Subgroup survival analyses according to PD-L1 and PD-L2 expression in the IHC cohort. d Subgroup survival analyses according to PD-L1 and PD-1 expression in the IHC cohort. e Subgroup survival analyses according to PD-L2 and PD-1 expression in the IHC cohortCC BY · PubMed Central
Fig. 3 The underlying mechanisms of the PD-1, PD-L1 and PD-L2 associations with prognosis. a Cluster analysis and heat map visualization of immune checkpoint-related genes, OS and HUVOS grade. b Heat map visualization of the differentially expressed genes between the PD-1 high-expression group and PD-1 low-expression group, c GSEA analysis of PD-1 and d gene annotation network analysis of the differentially expressed genes. e Heat map visualization of the differentially expressed genes between the PD-L1 high-expression group and PD-L1 low-expression group, f GSEA analysis of PD-L1 and g gene annotation network analysis of the differentially expressed genes. h Heat map visualization of the differentially expressed genes between the PD-L2 high-expression group and PD-L2 low-expression group, i GSEA analysis of PD-L2 and j gene annotation network analysis of the differentially expressed genes
Fig. 3 The underlying mechanisms of the PD-1, PD-L1 and PD-L2 associations with prognosis. a Cluster analysis and heat map visualization of immune checkpoint-related genes, OS and HUVOS grade. b Heat map visualization of the differentially expressed genes between the PD-1 high-expression group and PD-1 low-expression group, c GSEA analysis of PD-1 and d gene annotation network analysis of the differentially expressed genes. e Heat map visualization of the differentially expressed genes between the PD-L1 high-expression group and PD-L1 low-expression group, f GSEA analysis of PD-L1 and g gene annotation network analysis of the differentially expressed genes. h Heat map visualization of the differentially expressed genes between the PD-L2 high-expression group and PD-L2 low-expression group, i GSEA analysis of PD-L2 and j gene annotation network analysis of the differentially expressed genesCC BY · PubMed Central
Fig. 4 The expressions of PD-L1 and PD-L2 in osteosarcoma cell lines and nivolumab-suppressed osteosarcoma metastasis in vivo. a Western blotting analyses of PD-L1 and PD-L2 expression. NIH3T3 was used as the positive control. b Representative membranous expression of PD-L1 and PD-L2 in the KHOS cell line (red) compared with that of the isotype control (black) from the flow cytometry analysis. c The tumor growth curve of the nivolumab-treated and control groups. d Representative images of the primary tumors. e Metastatic frequency of the nivolumab-treated and control groups. f The number of metastatic nodules in the lungs from the nivolumab-treated and control groups is presented. g H&E staining of the lungs from the nivolumab-treated and control groups (magnification at × 16 and × 100). The lung metastases are indicated by the arrows. Data are presented as the mean ± S.D. (n = 5) ***P < 0.001 by Student’s t test
Fig. 4 The expressions of PD-L1 and PD-L2 in osteosarcoma cell lines and nivolumab-suppressed osteosarcoma metastasis in vivo. a Western blotting analyses of PD-L1 and PD-L2 expression. NIH3T3 was used as the positive control. b Representative membranous expression of PD-L1 and PD-L2 in the KHOS cell line (red) compared with that of the isotype control (black) from the flow cytometry analysis. c The tumor growth curve of the nivolumab-treated and control groups. d Representative images of the primary tumors. e Metastatic frequency of the nivolumab-treated and control groups. f The number of metastatic nodules in the lungs from the nivolumab-treated and control groups is presented. g H&E staining of the lungs from the nivolumab-treated and control groups (magnification at × 16 and × 100). The lung metastases are indicated by the arrows. Data are presented as the mean ± S.D. (n = 5) ***P < 0.001 by Student’s t testCC BY · PubMed Central
Fig. 5 Effect of the nivolumab treatment on TILs. a Flow cytometry analyses of TILs in tumors from the nivolumab-treated and control groups. b IHC analyses of CD4, CD8, PD-L1, PD-1, GZMB, and IFN-γ in the tumors and lungs of the nivolumab-treated and control groups (magnification at × 400). Data are presented as the mean ± S.D. (n = 5) **P < 0.01, ***P < 0.001 by Student’s t test
Fig. 5 Effect of the nivolumab treatment on TILs. a Flow cytometry analyses of TILs in tumors from the nivolumab-treated and control groups. b IHC analyses of CD4, CD8, PD-L1, PD-1, GZMB, and IFN-γ in the tumors and lungs of the nivolumab-treated and control groups (magnification at × 400). Data are presented as the mean ± S.D. (n = 5) **P < 0.01, ***P < 0.001 by Student’s t testCC BY · PubMed Central

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Authors
Zheng, B., Ren, T., Huang, Y., Sun, K., Wang, S., Bao, X., Liu, K., & Guo, W.
Affiliations
Peking University People's Hospital (CN)
Corresponding author
Guo, Wei
ORCID
Venue
Journal of Hematology & Oncology
Publisher
Springer Science and Business Media LLC
Published
2018-02-06
Volume
11
Issue
1
Pages
16-16
ISSN
1756-8722 (ISSN-L)
DOI
10.1186/s13045-018-0560-1
PMC
PMC5801803
OpenAlex
W2803454898
Cited by
151
References
45
Citations by year
2026: 9 · 2025: 17 · 2024: 18 · 2023: 19 · 2022: 22 · 2021: 20 · 2020: 29 · 2019: 9 · 2018: 8
FWCI
6.30
Type
journal article
Language
en
Update notices
correction (2018-03-12)
Open access
Licence
cc-by
Locations
  • Journal of Hematology & Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Natural Science Foundation of China (81572633, 81472509)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Sarcoma Diagnosis and Treatment
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
PD-L1, PD-L2, nivolumab, osteosarcoma, musculoskeletal tumors, immune checkpoint inhibitors, lung metastasis, humanized mice, CD8+ T cells, prognostic factors, chondrosarcoma, synovial sarcoma, giant cell tumor
MeSH terms
Antineoplastic Agents, Immunological, Nivolumab, Adult, Animals, Bone Neoplasms, Chondrosarcoma, Female, Giant Cell Tumors, Humans, Male, Middle Aged, Neoplasms, Connective Tissue, Osteosarcoma, Sarcoma, Synovial, Cell Line, Tumor, Mice, Young Adult, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Programmed Cell Death 1 Ligand 2 Protein

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