Abstract
Macrophages are one of the immune populations frequently found in colorectal tumors and high macrophage infiltration has been associated with both better and worst prognosis. Importantly, according to microenvironment stimuli, macrophages may adopt different polarization profiles, specifically the pro-inflammatory or M1 and the anti-inflammatory or M2, which display distinct functions. Therefore, concomitantly with the number of tumor-associated macrophages (TAMs), their characterization is fundamental to unravel their relevance in cancer. Here, we profiled macrophages in a series of 150 colorectal cancer (CRC) cases by immunohistochemistry, using CD68 as a macrophage lineage marker, CD80 as a marker of pro-inflammatory macrophages, and CD163 as a marker of anti-inflammatory macrophages. Quantifications were performed by computer-assisted analysis in the intratumoral region, tumor invasive front, and matched tumor adjacent normal mucosa (ANM). Macrophages, specifically the CD163+ ones, were predominantly found at the tumor invasive front, whereas CD80+ macrophages were almost exclusively located in the ANM, which suggests a predominant anti-inflammatory polarization of TAMs. Stratification according to tumor stage revealed that macrophages, specifically the CD163+ ones, are more prevalent in stage II tumors, whereas CD80+ macrophages are predominant in less invasive T1 tumors. Specifically in stage III tumors, higher CD68, and lower CD80/CD163 ratio associated with decreased overall survival. Importantly, despite the low infiltration of CD80+ cells in colorectal tumors, multivariate logistic regression revealed a protective role of these cells regarding the risk for relapse. Overall, this work supports the involvement of distinct microenvironments, present at the intra-tumor, invasive front and ANM regions, on macrophage modulation, and uncovers their prognostic value, further supporting the relevance of including macrophage profiling in clinical settings.
Highlights
A variety of non-malignant stromal cells present at the complex tumor microenvironment are active players in cancer progression [1]
CD68+ and CD163+ Cells Are Predominantly Found Within the Tumor Invasive Front Whereas CD80+ Cells Are Mainly Located in the Tumor Adjacent Normal Mucosa
Given the difficulty in accurately assessing macrophage number using the classical approach of counting cells under the microscope, macrophage populations were evaluated by digitally quantifying the percentage of immunoreactive area (IRA)%, to what was carried out by other groups (Supplementary Figure 1) [27, 28]
Summary
A variety of non-malignant stromal cells present at the complex tumor microenvironment are active players in cancer progression [1]. In the presence of factors such as lipopolysaccharide (LPS), interferon (IFN)-γ or tumor necrosis factor (TNF)-α [6], macrophages adopt a pro-inflammatory phenotype, with high antigen presenting capacity and production of cytokines such as interleukin (IL)-6, IL-12, TNF-α, IFN-γ, and reactive oxygen species (ROS) These cells are known for their bactericidal and pro-inflammatory functions [7]. As a consequence of the immunosuppressive tumor microenvironment, namely due to high IL-10 and TGF-β levels [9, 10], TAMs are reported to adopt features common to M2-like macrophages They generally produce growth factors, chemokines, and matrix metalloproteinases (MMPs), which act directly on cancer cells or in other stromal cells, leading to tumor growth, invasion, and metastasis [3]
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