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Characterization of Macrophages and Osteoclasts in the Osteosarcoma Tumor Microenvironment at Diagnosis: New Perspective for Osteosarcoma Treatment?

ABSTRACT: Biological and histopathological techniques identified osteoclasts and macrophages as targets of zoledronic acid (ZA), a therapeutic agent that was detrimental for patients in the French OS2006 trial. Conventional and multiplex immunohistochemistry of microenvironmental and OS cells were performed on biopsies of 124 OS2006 patients and 17 surgical ("OSNew") biopsies respectively. CSF-1R (common osteoclast/macrophage progenitor) and TRAP (osteoclast activity) levels in serum of 108 patients were correlated to response to chemotherapy and to prognosis. TRAP levels at surgery and at the end of the protocol were significantly lower in ZA+ than ZA- patients (p_adj = 0.0011; 0.0132). For ZA+-patients, an increase in the CSF-1R level between diagnosis and surgery and a high TRAP level in the serum at biopsy were associated with a better response to chemotherapy (p = 0.0091; p = 0.0251). At diagnosis, high CD163+ was associated with good prognosis, while low TRAP activity was associated with better overall survival in ZA- patients only. Multiplex immunohistochemistry demonstrated remarkable bipotent CD68+/CD163+ macrophages, homogeneously distributed throughout OS regions, aside osteoclasts (CD68+/CD163-) mostly residing in osteolytic territories and osteoid-matrix-associated CD68-/CD163+ macrophages. We demonstrate that ZA not only acts on harmful osteoclasts but also on protective macrophages, and hypothesize that the bipotent CD68+/CD163+ macrophages might present novel therapeutic targets.

SUBMITTER: Gomez-Brouchet A

PROVIDER: S-EPMC7866157 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Characterization of Macrophages and Osteoclasts in the Osteosarcoma Tumor Microenvironment at Diagnosis: New Perspective for Osteosarcoma Treatment?

Gomez-Brouchet Anne A Gilhodes Julia J Acker Nathalie Van NV Brion Regis R Bouvier Corinne C Assemat Pauline P Gaspar Nathalie N Aubert Sebastien S Guinebretiere Jean-Marc JM Marie Beatrice B Larousserie Frederique F Entz-Werlé Natacha N Pinieux Gonzague de G Mascard Eric E Gouin Francois F Brousset Pierre P Tabone Marie-Dominique MD Jimenez Marta M Le Deley Marie-Cecile MC Blay Jean-Yves JY Brugieres Laurence L Piperno-Neumann Sophie S Rédini Francoise F

Cancers 20210123 3

Biological and histopathological techniques identified osteoclasts and macrophages as targets of zoledronic acid (ZA), a therapeutic agent that was detrimental for patients in the French OS2006 trial. Conventional and multiplex immunohistochemistry of microenvironmental and OS cells were performed on biopsies of 124 OS2006 patients and 17 surgical ("OSNew") biopsies respectively. CSF-1R (common osteoclast/macrophage progenitor) and TRAP (osteoclast activity) levels in serum of 108 patients were ...[more]

PMID: 33498676

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Project description:BackgroundOsteosarcoma (OS), the commonest primary malignant bone tumor, is mainly seen in children and teenagers. LINC00960, a newly discovered long intergenic non-protein coding RNA, has been shown to be important in certain cancers. The objective of this study was to assess LINC00960's prognostic and therapeutic value and analyze its mechanism of action in osteosarcoma.MethodsWith the transcriptome information of 85 osteosarcomas from the TARGET database, the Cox regression analyses, K-M curve, and ROC curve, were conducted for survival and prognostic analysis. The functional analysis was conducted using GO, KEGG, GSEA, and GSVA. The ESTIMATE, ssGSEA, MCP-counter, ImmuCellAI algorithms, and immune checkpoint correlation analysis were performed for immune-related analysis. The single-cell RNA sequencing data of 6 osteosarcoma patients was obtained from the Gene Expression Omnibus database. The Tumor Immune Dysfunction and Exclusion algorithm and the "pRRophetic" R package were performed to predict the response to immunotherapy and chemotherapy.ResultsLINC00960 overexpression is associated with osteosarcoma metastasis and poor prognosis. Based on the LINC00960 expression, the nomogram prediction model was created, which showed good accuracy and precision to predict the overall survival of osteosarcoma. Single-cell and immune-related analysis showed that LINC00960 is mainly highly expressed in the tumor-exhausted CD8 T cells in osteosarcoma. In osteosarcoma, the expression of LIC00960 was favorably connected with immune checkpoint-related genes and negatively correlated with immune infiltration. TIDE analysis indicated that low LINC00960 expression patients might have a better response to immunotherapy. Drug sensitivity analysis showed that high LINC00960 expression patients might have better responses to Bleomycin and Doxorubicin.ConclusionLINC00960 has the potential to be a novel biomarker for predicting overall survival in osteosarcoma patients and to guide more individualized treatment and clinical decision-making.

Project description:IntroductionOsteosarcoma (OS) is a highly aggressive bone malignancy with a poor prognosis, mainly in children and adolescents. Immunogenic cell death (ICD) is classified as a type of programmed cell death associated with the tumor immune microenvironment, prognosis, and immunotherapy. However, the feature of the ICD molecular subtype and the related tumor microenvironment (TME) and immune cell infiltration has not been carefully investigated in OS.MethodsThe ICD-related genes were extracted from previous studies, and the RNA expression profiles and corresponding data of OS were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus database. The ICD-related molecular subtypes were classed by the "ConsensusclusterPlus" package and the construction of ICD-related signatures through univariate regression analysis. ROC curves, independent analysis, and internal validation were used to evaluate signature performance. Moreover, a series of bioinformatic analyses were used for Immunotherapy efficacy, tumor immune microenvironments, and chemotherapeutic drug sensitivity between the high- and low-risk groups.ResultsHerein, we identified two ICD-related subtypes and found significant heterogeneity in clinical prognosis, TME, and immune response signaling among distinct ICD subtypes. Subsequently, a novel ICD-related prognostic signature was developed to determine its predictive performance in OS. Also, a highly accurate nomogram was then constructed to improve the clinical applicability of the novel ICD-related signature. Furthermore, we observed significant correlations between ICD risk score and TME, immunotherapy response, and chemotherapeutic drug sensitivity. Notably, the in vitro experiments further verified that high GALNT14 expression is closely associated with poor prognosis and malignant progress of OS.DiscussionHence, we identified and validated that the novel ICD-related signature could serve as a promising biomarker for the OS's prognosis, chemotherapy, and immunotherapy response prediction, providing guidance for personalized and accurate immunotherapy strategies for OS.

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Dataset Information

Characterization of Macrophages and Osteoclasts in the Osteosarcoma Tumor Microenvironment at Diagnosis: New Perspective for Osteosarcoma Treatment?

Publications

Characterization of Macrophages and Osteoclasts in the Osteosarcoma Tumor Microenvironment at Diagnosis: New Perspective for Osteosarcoma Treatment?

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