Stromal Macrophage Expressing CD204 is Associated with Tumor Aggressiveness in Lung Adenocarcinoma
ABSTRACT 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.
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ABSTRACT: Solid tumors, beyond mere accumulation of cancer cells, form a complex ecosystem consisting of normal epithelial cells, fibroblasts, blood and lymphatic vessels, structural components and infiltrating hematopoietic cells including myeloid and lymphoid elements that impact tumor growth, spreading and clinical outcome. The composition of the immune microenvironment is diverse, including various populations of T cells, B cells, dendritic cells, natural killer cells, myeloid-derived suppressor cells, neutrophils or macrophages. The immune contexture describes the density, location and organization of these immune cells within solid tumors. In lung cancer, which is the deadliest type of cancer, and particularly in non-small cell lung cancer, its most prevalent form, recent reports have described some of the interactions between the tumor and the host. These data, in addition to recently published articles in various types of tumors, provide a greater understanding of the tumor/host microenvironment interaction and stimulate the development of prognostic and predictive biomarkers, the identification of novel target antigens for therapeutic intervention, and the implementation of tools for long-term management of cancer patients.American Journal of Respiratory and Critical Care Medicine 11/2014; 191(4). DOI:10.1164/rccm.201409-1671PP · 11.99 Impact Factor
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ABSTRACT: Previous study has revealed that tumor-associated macrophages (TAMs) correlate with response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC). In the present study, we further determined that M2-TAMs, but not M1-TAMs, are related to the treatment response to EGFR-TKIs in advanced NSCLC and may be an independent predictor of survival. Eighty-eight advanced lung adenocarcinoma patients treated with a second-line EGFR-TKI were involved in this study. M2-TAMs counts but not M1-TAMs were significantly higher in patients with progressive disease than in those without (P < 0.001). A trend also remained in patients with known EGFR status (n = 61) and those with mutant EGFR (n = 49). High M2-TAMs counts were shown to be significantly related to poor progression-free survival (PFS) and overall survival (OS) in all patients, or subsets of patients with known EGFR status or patients with EGFR mutation (all P < 0.05). Multivariate Cox analyses showed that high M2-TAMs counts and EGFR mutations were both independent factors associated with PFS and OS (P < 0.05). Overall, we revealed that M2- but not M1-TAMs are related to the response of EGFR-TKIs treatment irrespective of EGFR mutation and can independently predict survival in advanced lung adenocarcinoma treated with a second-line EGFR-TKI.Medical Oncology 08/2014; 31(8):127. DOI:10.1007/s12032-014-0127-0 · 2.06 Impact Factor
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ABSTRACT: There is growing evidence that generation of adenosine from ATP, which is mediated by the CD39/CD73 enzyme pair, predetermines immunosuppressive and proangiogenic properties of myeloid cells. We have previously shown that the deletion of the TGF-β type II receptor gene (Tgfbr2) expression in myeloid cells is associated with decreased tumor growth, suggesting protumorigenic effect of TGF-β signaling. In this study, we tested the hypothesis that TGF-β drives differentiation of myeloid-derived suppressor cells into protumorigenic terminally differentiated myeloid mononuclear cells (TDMMCs) characterized by high levels of cell-surface CD39/CD73 expression. We found that TDMMCs represent a major cell subpopulation expressing high levels of both CD39 and CD73 in the tumor microenvironment. In tumors isolated from mice with spontaneous tumor formation of mammary gland and conditional deletion of the type II TGF-β receptor in mammary epithelium, an increased level of TGF-β protein was associated with further increase in number of CD39(+)CD73(+) TDMMCs compared with MMTV-PyMT/TGFβRII(WT) control tumors with intact TGF-β signaling. Using genetic and pharmacological approaches, we demonstrated that the TGF-β signaling mediates maturation of myeloid-derived suppressor cells into TDMMCs with high levels of cell surface CD39/CD73 expression and adenosine-generating capacity. Disruption of TGF-β signaling in myeloid cells resulted in decreased accumulation of TDMMCs, expressing CD39 and CD73, and was accompanied by increased infiltration of T lymphocytes, reduced density of blood vessels, and diminished progression of both Lewis lung carcinoma and spontaneous mammary carcinomas. We propose that TGF-β signaling can directly induce the generation of CD39(+)CD73(+) TDMMCs, thus contributing to the immunosuppressive, proangiogenic, and tumor-promoting effects of this pleiotropic effector in the tumor microenvironment.The Journal of Immunology 08/2014; 193(6). DOI:10.4049/jimmunol.1400578 · 5.36 Impact Factor