53. Significance of M1-polarized tumor-associated macrophages in gastric cancer

Background: The immune system plays a dual role in cancer not only by suppressing tumor growth but also by promoting tumor progression. Macrophages, as major components of infiltrated immune cells to tumors, play a complicated and multifaceted role in different microenvironments. Plasticity is a hallmark of the monocyte–macrophage lineage. There are two statuses of macrophage activation, M1 and M2 macrophages, mirroring the T helper type 1 and 2 (Th1 and Th2) nomenclature. In general, classically activated macrophages (M1) are described as pro-inflammatory and tumor resistant; alternatively activated macrophages (M2) are more prone to immunoregulatory and protumorigenic activities. We investigated the correlation between tumor-associated macrophages (TAMs) and the prognosis of patients with gastric cancers.
Methods: Mac rophage polar ization wa s ana l y zed immunohistochemically in 223 patients with gastric cancer (GC). Macrophage density was classified as high or low using the median count as a cutoff, and the densities of macrophages with different phenotypes were correlated with clinicopathologic factors and survival. The following clinical characteristics evaluated by reviewing medical charts and pathology records were included in the analyses: Gender, age, tumor location, Lauren classification, lymphovascular invasion, lymph node metastasis, and depth of invasion. All GCs were staged according to the seventh edition of the UICC/AJCC TNM staging system.
Results: In this study, no significant correlation was found between TAM density and clinicopathologic factors. Significantly different densities of M1 macrophages were found in patients with different depth of wall invasion (P=0.006) and lymph node metastasis (P=0.017). The survival rate of patients with high densities of TAMs and M1 macrophages was significantly higher than that of patients with low densities of both macrophage types. For our multivariate Cox regression analyses, the factors examined included tumor location, lymphovascular invasion, depth of wall invasion, lymph node metastasis, density of CD68 (+) and Inos (+) macrophages. Based on our previous findings regarding patients with GC, depth of wall invasion, lymph node metastasis and density of CD68 (+) macrophages seem to be independent prognostic factors. However, the density of iNOS (+) macrophages was not an independent prognostic factor (P=0.2).
Conclusions: We identified intratumoral TAM (CD68-positive) density as an independent prognostic factor for GC regardless of polarization. Moreover, two distinct macrophage phenotypes coexist in GC, and mixed phenotype macrophages are also found. Although the majority of TAMs are M2-polarized, M2 macrophage density did not correlate with clinicopathologic factors or prognosis. We also demonstrated that high rates of iNOS-positive immunostaining in macrophages correlate with lymph node metastasis, suggesting that M1 macrophages might be useful biomarkers for immune system status. As a large number of natural and synthetic products can activate the immune response and induce nonspecific inflammation that could inhibit cancer progression, we have identified a potential new approach for anticancer drug development.