Small oral squamous cell carcinomas with nodal lymphogenic metastasis show increased infiltration of M2 polarized macrophages – An immunohistochemical analysis

Weber, Manuel; Büttner‐Herold, Maike; Hyckel, Peter; Moebius, Patrick; Distel, Luitpold; Ries, Jutta; Amann, Kerstin; Neukam, Friedrich Wilhelm; Wehrhan, Falk

doi:10.1016/j.jcms.2014.01.035

Cited by 74 publications

(78 citation statements)

References 35 publications

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“…This has to be interpreted considering the results of our previous study analyzing the macrophage polarization in oscc tumor tissue [26]. A correlation of the macrophage polarization of the primary tumor with the occurrence of lymph node metastases was shown [26]. Considering the previous results in conjunction with the results of the current study it can be concluded that the formation of metastases is triggered by the primary tumor and not by the lymph nodes.…”

Section: Discussionsupporting

confidence: 74%

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Increased malignancy of oral squamous cell carcinomas (oscc) is associated with macrophage polarization in regional lymph nodes – an immunohistochemical study

Wehrhan

Büttner‐Herold

Hyckel³

et al. 2014

BMC Cancer

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BackgroundIt is largely accepted that specific immunological parameters in solid malignancies are associated with patient’s prognosis. Recently a correlation of macrophage polarization with histomorphological parameters could also be shown in oral squamous cell carcinoma (oscc). The observed tumor derived peripheral immune tolerance could be associated with the macrophage polarization in regional tumor draining lymph nodes.So far there are no studies analyzing the macrophage polarization in cervical lymph nodes of oscc patients. In the present study we aimed to correlate macrophage polarization in different anatomical lymph node compartments of patients diagnosed with oscc with histopathologic parameters of the primary tumor (T-, N-, L-, V-, Pn-status, grading).MethodsTumor free (n = 37) and metastatic (n = 17) lymph nodes of T1 and T2 oscc patients were processed for immunohistochemistry to detect CD68, CD11c, CD163 and MRC1 positive cells. Samples were digitized using whole slide imaging and the number of cells expressing the aforementioned markers in the region of interest quantitatively analyzed.ResultsThe malignancy of the primary tumor (defined by T-, L-, Pn-status, grading) correlated with the lymph node macrophage polarization. L1 and Pn1 tumor cases displayed a significantly (p < 0.05) decreased M1 and increased M2 polarization in the sinus of the lymph nodes. G3 cases presented a significantly (p < 0.05) increased M2 polarization in the sinus compared to G2 cases. T2 tumors had significantly (p < 0.05) increased M2 polarization in the interfollicular zone of regional lymph nodes compared to T1 tumors. Metastatic and non-metastatic lymph nodes did not differ regarding their macrophage polarization.ConclusionsThe current study revealed for the first time an influence of oscc on the macrophage polarization in regional lymph nodes. Markers of malignant behavior in the primary tumor were associated with a shift of macrophage polarization in lymph nodes from the anti-tumoral M1 type to the tumor-promoting M2 type. As tumor free and metastatic lymph nodes did not differ in terms of their macrophage polarization pattern, there must be other factors influencing the location for lymph node metastasis formation.

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Section: Discussionsupporting

confidence: 74%

“…An increased M2 polarization in the epithelial tumor compartment was associated with the occurrence of lymph node metastasis [26]. …”

Section: Introductionmentioning

confidence: 99%

Increased malignancy of oral squamous cell carcinomas (oscc) is associated with macrophage polarization in regional lymph nodes – an immunohistochemical study

Wehrhan

Büttner‐Herold

Hyckel³

et al. 2014

BMC Cancer

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“…A number of studies have reported that high TAM levels within tumors were linked with local inflammation, angiogenesis, and poor prognosis for cancer patients (27,(42)(43)(44). The present study showed that high levels of scIgGs in breast tumors were also associated with high TAM levels.…”

Section: Elevated Sciggs Parallel Increased Levels Of Mmps In Breastsupporting

confidence: 68%

Dysfunctional Antibodies in the Tumor Microenvironment Associate with Impaired Anticancer Immunity

Zhang

Deng

Fan

et al. 2015

Clinical Cancer Research

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Purpose: Studies have demonstrated that cancer-associated matrix metalloproteinases (MMP) can generate single peptide bond cleavages in the hinge region of immunoglobulin G 1 (IgG1). This study investigated the cleavage of endogenous IgGs by MMPs in the tumor microenvironment and the consequences of the IgG hinge cleavage for humoral immunity.Experimental Design: We investigated the occurrence of single peptide bond cleaved IgGs (scIgG) in tumor tissues and plasma samples collected from a cohort of breast cancer patients (n ¼ 60). Samples from healthy people (n ¼ 20) were used as the control. Antibody hinge cleavage was detected by multiple assays, including IHC, ELISA, and flow cytometry. A correlation analysis was conducted between scIgG levels and patient clinical parameters.Results: Levels of scIgGs in tumors were significantly higher than in normal tissues. In addition, scIgG levels in tumors were enriched compared with that in the plasma of the same patients. The appearance of scIgGs in tumor tissues was associated with altered host IgG content and decreased IgG1. Increased tumor scIgGs were found to be positively correlated with adverse clinical factors, such as elevated tumor-associated macrophages, increased expression of MMP9 and other MMPs, and local metastasis to axillary lymph nodes.Conclusions: The study contributes to mounting evidence for the presence of hinge-cleaved antibodies with reduced Fc immune effector function in the tumor microenvironment. The results highlight a link between tumor scIgGs and poor patient outcomes, and reveal a component of compromised humoral immunity within tumors that could point to new immunotherapeutic strategies to rescue host immunity. Clin Cancer Res; 21(23); 5380-90.Ó2015 AACR.

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“…Besides, study found that the NF-κB pathway might involve in the induction of M2 phenotype macrophage polarization by OSCC cells [17]. In addition, macrophage polarization influences progression and survival of solid malignancies, including OSCC [18, 19]. …”

Section: Introductionmentioning

confidence: 99%

Signal regulatory protein α associated with the progression of oral leukoplakia and oral squamous cell carcinoma regulates phenotype switch of macrophages

Zhang

et al. 2016

Oncotarget

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Signal regulatory protein a (SIRPa) is a cell-surface protein expressed on macrophages that are regarded as an important component of the tumor microenvironment. The expression of SIRPa in oral leukoplakia (OLK) and oral squamous cell carcinoma (OSCC), and further explored the role of SIRPa on the phenotype, phagocytosis ability, migration, and invasion of macrophages in OSCC were investigated. The expression of SIRPa in OLK was higher than in OSCC, correlating with the expression of CD68 and CD163 on macrophages. After cultured with the conditioned media of oral cancer cells, the expression of SIRPa on THP-1 cells was decreased gradually. In co-culture system, macrophages were induced into M2 phenotype by oral cancer cells. Blockade of SIRPa inhibited phagocytosis ability and IL-6, TNF-a productions of macrophages. In addition, the proliferation, migration, and IL-10, TGF-β productions of macrophages were upregulated after blockade of SIRPa. Macrophages upregulated the expression of SIRPa and phagocytosis ability, and inhibited the migration and invasion when the activation of NF-kB was inhibited by pyrrolidine dithiocarbamate ammonium (PDTC). Hence, SIRPa might play an important role in the progression of OLK and oral cancer, and could be a pivotal therapeutic target in OSCC by regulating the phenotype of macrophages via targeting NF-kB.

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Small oral squamous cell carcinomas with nodal lymphogenic metastasis show increased infiltration of M2 polarized macrophages – An immunohistochemical analysis

Cited by 74 publications

References 35 publications

Increased malignancy of oral squamous cell carcinomas (oscc) is associated with macrophage polarization in regional lymph nodes – an immunohistochemical study

Increased malignancy of oral squamous cell carcinomas (oscc) is associated with macrophage polarization in regional lymph nodes – an immunohistochemical study

Dysfunctional Antibodies in the Tumor Microenvironment Associate with Impaired Anticancer Immunity

Signal regulatory protein α associated with the progression of oral leukoplakia and oral squamous cell carcinoma regulates phenotype switch of macrophages

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