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

Gomez-Brouchet, Anne and Gilhodes, Julia and Van Acker, Nathalie and Brion, Regis and Bouvier, Corinne and Assemat, Pauline and Gaspar, Nathalie and Aubert, Sébastien and Guinebretiere, Jean-Marc and Marie, Béatrice and Larousserie, Frederique and Entz-Werlé, Natacha and de Pinieux, Gonzague and Mascard, Eric and Gouin, François and Brousset, Pierre and Tabone, Marie-Dominique and Jimenez, Marta and Le Deley, Marie-Cécile and Blay, Jean-Yves and Brugieres, Laurence and Piperno-Neumann, Sophie and Rédini, Françoise Characterization of Macrophages and Osteoclasts in the Osteosarcoma Tumor Microenvironment at Diagnosis: New Perspective for Osteosarcoma Treatment? (2021) Cancers, 13 (3). ISSN 2072-6694

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Official URL: https://doi.org/10.3390/cancers13030423


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 (padj = 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.

Item Type:Article
Additional Information:Licence : CC BY 4.0
HAL Id:hal-03141387
Audience (journal):International peer-reviewed journal
Uncontrolled Keywords:
Institution:French research institutions > Centre National de la Recherche Scientifique - CNRS (FRANCE)
Université de Toulouse > Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE)
Université de Toulouse > Université Toulouse III - Paul Sabatier - UT3 (FRANCE)
Laboratory name:
BMS foundation (France) - Société Française des Cancers et Leucémies de l’Enfant - SFCE (France) - Association Etoile de Martin (France)
Deposited On:15 Feb 2021 10:31

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