Dysregulation of macrophage polarization is associated with the metastatic process in osteosarcoma

Abstract

Osteosarcoma (OS) is the most common bone sarcoma in adolescents, and has poor prognosis. A vicious cycle is established between OS cells and their microenvironment in order to facilitate the tumor growth and cell spreading. The present work aims to better characterize the tumor microenvironment in OS in order to identify new therapeutic targets relating to metastatic process. Tissue microarrays of pre-chemotherapy OS biopsies were used for characterizing the tumor niche by immunohistochemistry. Parameters studies included: immune cells (M1, M2-subtypes of tumor-associated macrophages (TAM); T, B lymphocytes; mast cells), vascularization (endothelial, perivascular cells), OPG, RANKL, and mitotic index. Two groups of patients were defined, 22 localized OS (OS Meta-) and 28 metastatic OS (OS Meta+). The OS Meta- group was characterized by a higher infiltration of INOS+ M1-polarizedmacrophages and upregulated OPG immunostaining. OS Meta+ tumors showed a significant increase in CD146+ cells. INOS+ M1-macrophages were correlated with OPG staining, and negatively with the presence of metastases. CD163+ M2-macrophages were positively correlated with CD146+ cells. In multivariate analysis, INOS and OPG were predictive factors for metastasis. An older age, non-metastatic tumor, good response to chemotherapy, and higher macrophage infiltration were significantly associated with better overall survival. TAMs are associated with better overall survival and a dysregulation of M1/M2 polarized-macrophages in favor of M1 subtype was observed in non-metastatic OS.

The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

“…Immune infiltrates composed by heterogenous cell populations such as myeloid and lymphoid cells, which play a role in innate and adaptive immunity, have been detected in osteosarcoma [41,42] (Figure 1, Figure 2). Whether myeloid (monocytes, macrophages, dendritic cells) and T-lymphocytes are the main populations represented, few B lymphocytes and rare mast cells have also been identified and may be related to tumor growth [41].…”

“…Whether myeloid (monocytes, macrophages, dendritic cells) and T-lymphocytes are the main populations represented, few B lymphocytes and rare mast cells have also been identified and may be related to tumor growth [41]. CD20 + B lymphocytes cells showed a modest disseminated infiltrate [42], and mast cells (CD117 + , tryptase + ) are modestly detected in the tumor mass [41,42], and mainly observed at the bone-tumor interface where osteolysis was occurring [41]. Osteosarcoma cells maintain mast cell viability and activities [43], which could be a source of RANKL [44].…”

“…In preclinical models of osteosarcoma, M2-type macrophages were correlated to an increase of tumor growth, vascularization and metastatic dissemination [69]. Whether on the one hand the number of macrophages correlated with the number of blood vessels (CD31 + ) [69] and on the other hand CD163 + M2-TAMs with CD146 + perivascular cells [42], the vascular density did not correlated with prognosis [70]. The prognostic relevance of the vascular density in osteosarcoma is controversial.…”

“…T-lymphocytes constitute the second most represented cell-type infiltrate in osteosarcoma tissues [41,42] (Figure 1). Recent estimation showed that Tumor-Infiltrating Lymphocytes (TILs) are detectable in 75% of osteosarcoma with a peak around 86% in metastases [78].…”

Metastatic immune infiltrates correlate with those of the primary tumour in canine osteosarcoma

“…To the authors' knowledge macrophages have not been evaluated in metastatic OSA in either dogs or humans. Reports in both species, however, tend to support the notion that macrophages within the primary tumour have an anti‐metastatic role in OSA . Furthermore, macrophages are thought to be a key mediator of the efficacy of liposomal muramyl tripeptidyl phosphatidylethanolamine (L‐MTP‐PE), a treatment that has prolonged survival in cOSA and hOSA clinical trials .…”