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Clinical significance of CD163? tumor-associated macrophages in patients with adult T-cell leukemia/lymphoma.

ABSTRACT: In several malignant tumors including lymphoma, macrophages that infiltrate tumor tissues are called tumor-associated macrophages (TAMs). We discovered that TAMs, especially the CD163? alternatively activated phenotype (M2), were closely involved with progression of adult T-cell leukemia/lymphoma (ATLL). We used CD68 (a pan-macrophage marker) and CD163 (an M2 marker) to immunostain 58 ATLL samples. Statistical analyses showed that a high number of CD68? TAMs and an increased percentage of CD163? cells among the TAMs were associated with a worse clinical prognosis; multivariate analysis indicated that the percentage of CD163? cells was an independent prognostic factor. We also carried out in vitro coculture experiments with ATLL cell lines (ATN-1 and TL-Mor) and monocyte-derived macrophages and found that direct coculture with M2 macrophages significantly increased BrdU incorporation into ATLL cell lines. A cytokine array analysis showed that macrophage-derived soluble factors including C5a, tumor necrosis factor-?, growth-related oncogene-?, CCL1/I-309, and interleukin-6 stimulated ATLL cell lines. CD163 expression in macrophages was strongly induced by direct contact with ATN-1 cells, and downregulation of CD163 in macrophages significantly suppressed growth of cocultured ATN-1 cells. These results suggest that interaction between M2 macrophages and lymphoma cells may be an appropriate target in treatment of patients with ATLL.

SUBMITTER: Komohara Y

PROVIDER: S-EPMC7657152 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Clinical significance of CD163⁺ tumor-associated macrophages in patients with adult T-cell leukemia/lymphoma.

Komohara Yoshihiro Y Niino Daisuke D Saito Yoichi Y Ohnishi Koji K Horlad Hasita H Ohshima Koichi K Takeya Motohiro M

Cancer science 20130509 7

In several malignant tumors including lymphoma, macrophages that infiltrate tumor tissues are called tumor-associated macrophages (TAMs). We discovered that TAMs, especially the CD163⁺ alternatively activated phenotype (M2), were closely involved with progression of adult T-cell leukemia/lymphoma (ATLL). We used CD68 (a pan-macrophage marker) and CD163 (an M2 marker) to immunostain 58 ATLL samples. Statistical analyses showed that a high number of CD68⁺ TAMs and an increased percentage of CD163⁺ ...[more]

PMID: 23557330

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Project description: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.

Project description:BackgroundLymphoma-associated macrophages (LAMs) are key components in the lymphoma microenvironment, which may impact disease progression and response to therapy. There are two major subtypes of LAMs, CD68+ M1 and CD163+ M2. M2 LAMs can be transformed from M1 LAMs, particularly in certain diffuse large B-cell lymphomas (DLBCL). While mantle cell lymphoma (MCL) is well-known to contain frequent epithelioid macrophages, LAM characterization within MCL has not been fully described. Herein we evaluate the immunophenotypic subclassification, the expression of immune checkpoint molecule PD-L1, and the prognostic impact of LAMs in MCL.Materials and methodsA total of 82 MCL cases were collected and a tissue microarray block was constructed. Immunohistochemical staining was performed using CD68 and CD163, and the positive cells were recorded manually in four representative 400× fields for each case. Multiplexed quantitative immunofluorescence assays were carried out to determine PD-L1 expression on CD68+ M1 LAMs and CD163+ M2 LAMs. In addition, we assessed Ki67 proliferation rate of MCL by an automated method using the QuPath digital imaging analysis. The cut-off points of optimal separation of overall survival (OS) were analyzed using the X-Tile software, the SPSS version 26 was used to construct survival curves, and the log-rank test was performed to calculate the p-values.ResultsMCL had a much higher count of M1 LAMs than M2 LAMs with a CD68:CD163 ratio of 3:1. Both M1 and M2 LAMs were increased in MCL cases with high Ki67 proliferation rates (>30%), in contrast to those with low Ki67 (<30%). Increased number of M1 or M2 LAMs in MCL was associated with an inferior OS. Moreover, high expression of PD-L1 on M1 LAMs had a slightly better OS than the cases with low PD-L1 expression, whereas low expression of PD-L1 on M2 LAMs had a slightly improved OS, although both were not statistically significant.ConclusionsIn contrast to DLBCL, MCL had a significantly lower rate of M1 to M2 polarization, and the high levels of M1 and M2 LAMs were associated with poor OS. Furthermore, differential PD-L1 expressions on LAMs may partially explain the different functions of tumor-suppressing or tumor-promoting of M1 and M2 LAMs, respectively.

Dataset Information

Clinical significance of CD163? tumor-associated macrophages in patients with adult T-cell leukemia/lymphoma.

Publications

Clinical significance of CD163⁺ tumor-associated macrophages in patients with adult T-cell leukemia/lymphoma.

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