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

Anne Gomez-Brouchet 1 Julia Gilhodes 2 Nathalie van Acker 2 Regis Brion 3 Corinne Bouvier 4 Pauline Assemat 5 Nathalie Gaspar 6, 7, 8 Sébastien Aubert 9 Jean-Marc Guinebretiere 10 Béatrice Marie 11 Frederique Larousserie 12 Natacha Entz-Werlé 13 Gonzague de Pinieux Eric Mascard 8 François Gouin 14 Pierre Brousset 2 Marie-Dominique Tabone 15 Marta Jimenez 16 Marie-Cécile Le Deley 17 Jean-Yves Blay 18 Laurence Brugieres 8 Sophie Piperno-Neumann 10 Françoise Rédini 19
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.
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Submitted on : Monday, February 15, 2021 - 11:31:12 AM
Last modification on : Tuesday, September 21, 2021 - 4:20:08 PM
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Anne Gomez-Brouchet, Julia Gilhodes, Nathalie van Acker, Regis Brion, Corinne Bouvier, et al.. Characterization of Macrophages and Osteoclasts in the Osteosarcoma Tumor Microenvironment at Diagnosis: New Perspective for Osteosarcoma Treatment?. Cancers, MDPI, 2021, 13 (3), pp.13030423. ⟨10.3390/cancers13030423⟩. ⟨hal-03141387⟩



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