Stromal Macrophage Expressing CD204 is Associated with Tumor Aggressiveness in Lung Adenocarcinoma
Tumor tissue is composed of variable numbers of cancer cells and stromal cells, and tumor-associated macrophages are recruited into cancer-induced stroma and produce a specific microenvironment. Alternatively, activated macrophages (M2 phenotype) are known to be related to tumor progression and outcome, and CD204 has been reported to be expressed in M2 macrophages in some tumors.
To investigate whether CD204-positive macrophages reflect tumor aggressiveness in adenocarcinoma of the lung, we investigated the relationships between the numbers of CD204-positive stromal macrophages and both clinicopathological features and outcome in 170 consecutive resected cases. We also examined the relationships between the numbers of CD204-positive macrophages and the expression levels of cytokines involved in the migration and differentiation of M2 macrophages.
The numbers of CD204-positive macrophages were significantly correlated with several prognostic factors. The log-rank test showed a significant association between the numbers of CD204-positive macrophages and a poor outcome (p = 0.0073), whereas the numbers of macrophages expressing CD68, a pan-macrophage/monocyte marker, were of marginal prognostic significance (p = 0.0789). We evaluated associations between the levels of expression of the cytokines IL-6, IL-10, IL-12a, IL-12b, M-colony-stimulating factor, IFN-gamma-., and monocyte chemoattractant protein-1 in cancer tissue and the numbers of CD204-positive macrophages. The expression levels of IL-10 and monocyte chemoattractant protein-1, which are involved in differentiation, accumulation, and migration of M2 macrophages, were significantly correlated with the numbers of CD204-positive macrophages (p = 0.031 and p = 0.031, respectively).
These findings demonstrated that CD204-positive macrophages clearly reflect the tumor-promoting phenotype of tumor-associated macrophages in lung adenocarcinoma.
Available from: Satoshi Marumo
- "Recent studies have shown that macrophages in the tumor islets which are associated with a good prognosis are mainly of the M1 phenotype  . On the other hand, TAMs of the M2 phenotype, which are located in the tumor stroma, were correlated with lymph node metastasis and poor prognosis in lung adenocarcinoma   . In classical Hodgkin lymphoma, the correlation between the percentage of peripheral monocytes at diagnosis and number of CD163+ TAMs in lesional tissue was reported . "
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Increasing evidence suggests that an elevated peripheral monocyte count at presentation predicts a poor prognosis in various types of malignancy, including malignant lymphoma. In lung adenocarcinoma, tumor-associated macrophages (TAMs) were reported to be associated with a poor prognosis. However, it is unknown if an elevated peripheral monocyte count is associated with a poor prognosis in lung adenocarcinoma. This study assessed the prognostic impact of the preoperative peripheral monocyte count in lung adenocarcinoma.
Materials and methods:
We retrospectively analyzed 302 consecutive patients with lung adenocarcinoma who received curative resection at Kitano Hospital. The receiver operating characteristic (ROC) curve for the peripheral monocyte count was used to determine the cut-off value. The relations between peripheral monocyte counts and clinicopathological factors were assessed. We also evaluated the impacts of possible prognostic factors including the preoperative peripheral monocyte count on survival, using the two-tailed log-rank test and Cox proportional hazards model. In addition, immunohistochemical staining for CD68 was performed to evaluate the monocytes in primary tumors.
A peripheral monocyte count of 430mm(-3) was the optimal cut-off value for prognosis. An elevated peripheral monocyte count was significantly associated with sex, performance status, smoking history, chronic obstructive pulmonary disease and interstitial lung disease. The two-tailed log-rank test demonstrated that patients with an elevated peripheral monocyte count experienced a poorer recurrence-free survival (RFS) and overall survival (OS) (P=0.0063, P<0.0001, respectively). In the multivariate analysis an elevated peripheral monocyte count was shown to be an independent prognostic factor for the RFS and OS (HR: 1.765; 95% CI: 1.071-2.910; P=0.0258, HR: 4.339; 95% CI: 2.032-9.263; P=0.0001, respectively). Furthermore, numbers of the monocytes in primary tumors significantly correlated with peripheral monocyte counts (r=0.627, P<0.0001).
The preoperative peripheral monocyte count is an important prognostic factor for patients with lung adenocarcinoma after curative resection.
Available from: Zhihong Yuan
- "The inflammation present in tumor microenvironment is characterized by leukocyte infiltration which includes tumor-associated macrophages mast cells, dendritic cells, natural killer cells, neutrophils, eosinophils and lymphocytes 
. It is also increasingly recognized that interaction of cancer cells, macrophages, and inflammatory response in the tumor microenvironment may facilitate cancer cell invasion and metastasis 
. Previously, we have shown that resident lung macrophages are crucial effectors of susceptibility to metastatic lung cancer growth . "
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ABSTRACT: It is increasingly recognized that the tumor microenvironment plays a critical role in the initiation and progression of lung cancer. In particular interaction of cancer cells, macrophages, and inflammatory response in the tumor microenvironment has been shown to facilitate cancer cell invasion and metastasis. The specific molecular pathways in macrophages that immunoedit tumor growth are not well defined. Triggering receptor expressed on myeloid cells 1 (TREM-1) is a member of the super immunoglobulin family expressed on a select group of myeloid cells mainly monocyte/macrophages. Recent studies suggest that expression of TREM-1 in tumors may predict cancer aggressiveness and disease outcomes in liver and lung cancer however the mechanism of TREM-1 expression in the setting of cancer is not defined. In this study we demonstrate that tumor tissue from patients with non-small cell lung cancer show an increased expression of TREM-1 and PGE2. Immunohistochemistry and immunofluorescence confirmed that the expression of TREM-1 was selectively seen in CD68 positive macrophages. By employing an in vitro model we confirmed that expression of TREM-1 is increased in macrophages that are co-cultured with human lung cancer cells. Studies with COX-2 inhibitors and siCOX-2 showed that expression of TREM-1 in macrophages in tumor microenvironment is dependent on COX-2 signaling. These studies for the first time define a link between tumor COX-2 induction, PGE2 production and expression of TREM-1 in macrophages in tumor microenvironment and suggest that TREM-1 might be a novel target for tumor immunomodulation.
Available from: Sanne Lievense
- "On the other hand, TAMs of the M2 phenotype which are located in the tumor stroma have been related to treatment response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and were shown to be independent negative predictors of survival in advanced NSCLC treated with an EGFR- TKI . In addition, macrophages of the M2 immunosuppressive phenotype were correlated with lymph node metastasis and poor prognosis in NSCLC  . More specifically, several studies have shown a possible role for the expression of the immunosuppressive cytokine interleukin-10 (IL-10) by TAMs in the progression and prognosis of NSCLC  . "
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ABSTRACT: Tumor-associated macrophages (TAMs) can be abundantly present in numerous cancer types. Under influence of various stimuli in the tumor microenvironment TAMs develop into a tumor-inhibitory (M1) or tumor-promoting (M2) phenotype. Recently, the role of TAMs in tumor biology and their prognostic value in cancer has become a major topic of interest. In this review we will discuss the importance of TAMs in the pathogenesis and clinical outcome of lung cancer and mesothelioma patients. In addition, the potential of TAMs as therapeutic targets will be discussed.
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