Expression of M2-Polarized Macrophages is Associated with Poor Prognosis for Advanced Epithelial Ovarian Cancer

Abstract

Macrophages are polarized into two functionally distinct forms, M1 and M2, in response to different microenvironment. Tumor-associated macrophages (TAMs) generally have M2 phenotype and promote tumor progression. Few studies to date have described the infiltration of M2-polarized macrophages in ovarian cancer. We used two macrophages markers, CD68 and CD163, to analyze the expression of TAMs and to clarify the relationship between the M2 form and survival in advanced ovarian cancer. Clinical data of 110 patients with stages III-IV epithelial ovarian cancer at Sun Yat-sen University Cancer Center between 1999 and 2007 were retrospectively reviewed. Immunohistochemical staining of CD68 and CD163 was performed. Correlations between macrophage density and patient survival were analyzed. Our data showed that no significant difference was observed in survival between patients in the high- and the low-CD68 expression groups. In contrast, the progression-free survival (PFS) rates (p = 0.003) and overall survival (OS) rates (p = 0.004) were significantly higher in the low-CD163 expression group than in the high-CD163 expression group, respectively. Similarly, we also observed significantly improved 3-year PFS (49.8% vs. 11.0%, p < 0.001) and OS (77.4% vs. 45.0%, p < 0.001) rates in patients in the low-CD163/CD68 ratio group when compared with the high-CD163/CD68 ratio group. Multivariate analysis identified the density of CD163-positive cells as well as the ratio of CD163/CD68 as negative predictors for PFS and OS, respectively. Our results show that the infiltration of CD163-positive M2 macrophages as well as activation of macrophages towards the M2 phenotype may contribute to poor survival in advanced ovarian cancer.

Upregulation of IGF1 by tumor-associated macrophages promotes the proliferation and migration of epithelial ovarian cancer cells

“…The TME is a supportive and receptive tissue microenvironment undergoing a series of molecular and cellular changes to form metastatic-designated sites, or the fertile soil in preparation for metastatic tumor cell seed colonization, thus supporting tumor settlement in distant organs and promoting tumor metastasis (6)(7)(8). As the most common immune cells in the TME, TAMs infiltrate the TME in OC in large numbers and play an important role in the formation of the OC TME and education of OC cells to develop to become more malignant by secreting various factors, such as IL-6 and IDO (16,18,19,39,40). Indeed, therapeutic methods targeting TAMs have been demonstrated as effective for controlling OC.…”

“…In addition to the microenvironment within tumor tissues, TAMs are also distributed in some special organs and lymph nodes, associated with metastasis to these regions (13,14). TAMs infiltrate into OC tissues in large numbers (15)(16)(17), contributing to the progression of OC (18,19), thus negatively affecting the progression-free survival rates and overall survival rates of these patients (16). However, the precise mechanism of how TAMs contribute to the progression of OC remains unclear.…”

Overexpression of Semaphorin4D Indicates Poor Prognosis and Prompts Monocyte Differentiation toward M2 Macrophages in Epithelial Ovarian Cancer

“…Several studies had already proved that high M2 macrophage count indicated tumor more aggressive and poor prognosis, including breast cancer (Shabo et al, 2008), lung adenocarcinoma (Zhang et al, 2011), and classical Hodgkin's lymphoma (Sanchez-Espiridion et al, 2012). Moreover, Lan et al recently showed that the infiltration of CD163-positive M2 macrophages as well as activation of macrophages towards the M2 phenotype may contribute to poor survival in advanced ovarian cancer (Lan et al, 2013), which was consistent with our results that demonstrated that both high M2 macrophage count in primary tumor and percent in ascites were closely related to EOC patients with advanced stage and platinum resistant and refractory and suggested a shorter OS and PFS.…”

Role of tumor‐associated macrophages in human malignancies: friend or foe?

“…91 However, most reports analyzing CD68 + TAMs failed to demonstrate significant associations with prognosis. 92 In contrast, CD163 + M2-TAM density correlated significantly with poor prognosis. PFS and OS were significantly higher in the low-CD163 expression group than in the high-CD163 expression group.…”