Prognostic Implication of M2 Macrophages Are Determined by the Proportional Balance of Tumor Associated Macrophages and Tumor Infiltrating Lymphocytes in Microsatellite-Unstable Gastric Carcinoma

Abstract

Tumor associated macrophages are major inflammatory cells that play an important role in the tumor microenvironment. In this study, we investigated the prognostic significance of tumor associated macrophages (TAMs) in MSI-high gastric cancers using immunohistochemistry. CD68 and CD163 were used as markers for total infiltrating macrophages and M2-polarized macrophages, respectively. The density of CD68+ or CD163+ TAMs in four different areas (epithelial and stromal compartments of both the tumor center and invasive front) were analyzed in 143 cases of MSI-high advanced gastric cancers using a computerized image analysis system. Gastric cancers were scored as “0” or “1” in each area when the density of CD68+ and CD163+ TAMs was below or above the median value. Low density of CD68+ or CD163+ macrophages in four combined areas was closely associated with more frequent low-grade histology and the intestinal type tumor of the Lauren classification. In survival analysis, the low density of CD163+ TAMs was significantly associated with poor disease-free survival. In multivariate survival analysis, CD163+ TAMs in four combined areas, stromal and epithelial compartments of both tumor center and invasive front were independent prognostic indicator in MSI-high gastric cancers. In addition, the density of CD163+ TAMs correlated with tumor infiltrating lymphocytes (TILs). Our results indicate that the high density of CD163+ TAMs is an independent prognostic marker heralding prolonged disease-free survival and that the prognostic implication of CD163+ TAMs might be determined by the proportional balance of TAMs and TILs in MSI-high gastric cancers.

Deep inside of gastric signet-ring cell carcinoma

“…The presence of macrophages inside the tumor and in the metastatic lymph nodes testifies their role in promoting the tumor growth and diffusion through a neo-lymphoangiogenesis stimulated by the release of humoral vascular growth factors. The absence of any other type of inflammatory circulating cells in the primary tumor or in the metastatic lymph nodes supports this interpretation, suggesting a particular nature and role of these macrophages [12][13][14][15]. The evident neo-lymphangiogenesis that accompanies the development of SRC, correlates with the great invasiveness of this cancer.…”

Prognostic significance of tumor-associated macrophage infiltration in gastric cancer: a meta-analysis

“…Zhang et al (2015) and Wang et al (2011) identified M1 macrophages as CD11c + and CD68 + HLA − DR + IL10 − cells, respectively. M2 macrophages were recognized as CD163 + cells in three studies (Kawahara et al, 2010;Kim et al, 2015;Park et al, 2016), and as CD206 + and CD204 + cells in one study each (Lin et al, 2015;Zhang et al, 2015).…”

“…The full texts of 15 candidate articles were carefully reviewed, with three being excluded as a result (two with inadequate data and one having examined the same patient group as another study). Finally, 12 studies were included in the meta-analysis ( Figure 1; Ishigami et al, 2003;Ohno et al, 2005;Haas et al, 2009;Kawahara et al, 2010;Wang et al, 2011;Amoueian et al, 2015;Kim et al, 2015;Lin et al, 2015;Wu et al, 2015;Park et al, 2016;Zhang et al, 2015Zhang et al, , 2016. In total, 1388 patients from China, Taiwan, Korea, Iran, Japan, and Germany were included.…”

“…Four studies incorporated fewer than 100 patients, and three examined over 150 patients. Nine articles reported the prognostic value of total infiltrating TAMs (Ishigami et al, 2003;Ohno et al, 2005;Haas et al, 2009;Kawahara et al, 2010;Amoueian et al, 2015;Kim et al, 2015;Wu et al, 2015;Zhang et al, 2015Zhang et al, , 2016, whereas others focused on specific TAM polarization subsets. Immunohistochemistry was used to detect both total infiltrating TAMs and TAM polarization.…”

“…A variety of markers (including CD68, CD163, CD206, etc.) have been used to identify different TAM subsets in tumor tissues (Ishigami et al, 2003;Ohno et al, 2005;Haas et al, 2009;Kawahara et al, 2010;Wang et al, 2011;Kim et al, 2015;Lin et al, 2015;Wu et al, 2015;Zhang et al, 2015;Park et al, 2016;Zhang et al, 2016). Among them, CD68 is commonly used as a cell surface marker of total infiltrating TAMs.…”