Stromal Macrophage Expressing CD204 is Associated with Tumor Aggressiveness in Lung Adenocarcinoma

ArticleinJournal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 5(10):1507-15 · October 2010with19 Reads
DOI: 10.1097/JTO.0b013e3181eba692 · Source: PubMed
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.
    • "In addition to confirming these prior reports, our results clarified the prognostic significance of the CD8 + /CD204 + ratio. CD204 + macrophages are another set of immune suppressor cells (M2 phenotype) [45], and marked CD204 + macrophage infiltration is reportedly associated with a malignant phenotype or poor survival for several cancers including ESCC [26,[46][47][48]. Given the functions of M2 macrophages, such as producing immune suppressive cytokines and downregulating effector T cell activity [49, 50], not only the number of CD204 + cells but also the balance between CD8 + and CD204 + cells must be considered. "
    [Show abstract] [Hide abstract] ABSTRACT: Immunotherapy with anti-PD-1 antibody preliminarily showed promising efficacy for treating esophageal squamous cell carcinoma (ESCC). Herein, we used tissue microarrays and immunohistochemically analyzed PD-L1 and various tumor infiltrating immune cells (TIICs) in specimens from 196 ESCC patients who had undergone curative resection without preoperative therapy. PD-L1 expressions in tumor cells (TCs) and TIICs, as well as infiltration of lymphocytes (CD4+, CD8+, FOXP3+, and PD- 1+) and macrophages (CD68+ and CD204+), were evaluated. PD-L1 was expressed in TCs of 18.4% and in TIICs of 83.3% of these patients. PD-L1 expressions in TCs and TIICs were associated with significant infiltration of various TIIC types, especially CD8+ cells. PD-L1 expressions in both TCs and TIICs were significantly associated with favorable overall survival, and combining their levels enhanced prognostic accuracy. Prognostic impacts of PD-L1 expressions in TCs and TIICs, abundant PD-1+ cell infiltration, a high CD8+/FOXP3+ ratio, and the CD8+/CD204+ ratio remained significant after adjusting for clinicopathological factors. In conclusion, PD-L1 expression reflects anti-tumor immunity, and PD-1/PD-L1 expression and the ratio of infiltrating effector to immune suppressor cells have prognostic value. Therapeutic strategies inhibiting the PD-1/PD-L1 signal and immune suppressor cells are anticipated in ESCC patients.
    Full-text · Article · Jun 2016
    • "Moreover, TAMs in tumor nest were reported to be associated with better outcome of human lung cancer [5, 11,[16][17][18] 20]. Other studies showed that increased TAMs in tumor stroma were negatively correlated with the survival of lung cancer [5, 11,[16][17][18][19][20] 22]. Thus, further studies are needed to clarify the role of tumor-infiltrating TAMs, subsets and intratumoral distribution of TAMs in prognostic prediction of lung cancer. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Tumor-associated macrophages (TAMs) play a crucial role in the regulation of local inflammatory and immune response of tumor microenvironment, being associated with worse outcome of several solid tumors. But the prognostic value of tumor-infiltrating TAMs in lung cancer is still controversial. Methods: We conduct a meta-analysis of 3055 patients in 21 studies searched from PubMed and Medline to investigate the correlation between tumor-infiltrating TAMs, including distinct TAM subsets and tissue distribution, and survival of lung cancer. Survival data were computed into odds ratios (ORs) and pooled using Mantel-Haenszel random-effect model. All statistical tests were two-sided. Results: High density of tumor-infiltrating TAMs was significantly associated with worse overall survival (OS) at 3 years (OR = 2.45, 95% CI = 1.25 to 4.80, P = 0.009) and 5 years (OR = 2.04, 95% CI = 1.03 to 4.01, P = 0.04) of lung cancer. Results for disease free survival (DFS) were similar. M2 subset was associated with worse 3 year-OS and 5 year-OS, whereas M1 subset was associated with better 3-year OS and 5-year OS. Elevated TAM density in tumor stroma was associated with worse OS at 3 years and 5 years, while elevated TAMs in tumor islet/tumor stroma were associated with better OS at 3 years and 5 years. Conclusions: Increased tumor-infiltrating TAMs are associated with poor prognosis of lung cancer. M2 subset and TAMs in tumor stroma were associated with worse survival, while M1 subset and TAMs in tumor islet were associated with favorable survival of lung cancer.
    Full-text · Article · May 2016
    • "CD68 is the most commonly used marker for the study of TAMs. A total of 12 out of the 20 included studies used CD68 as macrophage marker [15, 18, 23, 24,[28][29][30][32][33][34][35][36], while the other 4 studies used CD68 in combination with other markers for the detection of TAMs [19,[25][26][27]. Unlike some other solid tumors, the total number of I+S CD68 + TAMs was not associated with survival in lung cancer patients, while low islet and high stromal CD68 + TAMs were both associated with poor OS. "
    [Show abstract] [Hide abstract] ABSTRACT: Tumor-associated macrophages (TAMs) are important components of cancer microenvironment. In the present study, we searched PubMed, Embase, Cochrane library and Web of Science to perform a meta-analysis of 20 studies including a total of 2,572 non-small cell lung cancer (NSCLC) patients, in order to determine the association between TAMs and NSCLC prognosis. The combined hazard ratio (HR) of 9 studies showed that the density of total CD68+ TAMs in the tumor islet and stroma was not associated with overall survival (OS) of the patients. However, the pooled HR of 4 studies showed that high density of CD68+ TAMs in the tumor islet predicted better OS, while the pooled HR of 6 studies showed that high density of CD68+ TAMs in the tumor stroma was associated with poor OS. A high islet/stroma ratio of CD68+ TAMs was associated with better OS. A high density of M1 TAMs in the tumor islet was associated with better OS, while a high density of M2 TAMs in the tumor stroma predicted poor OS. These findings suggest that, although the density of total CD68+ TAMs is not associated with OS, the localization and M1/M2 polarization of TAMs are potential prognostic predictors of NSCLC.
    Full-text · Article · Apr 2016
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