Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma.

To evaluate and characterize macrophage populations (M1/M2) in the tumor microenvironment of oral cavity squamous cell carcinoma (OCSCC). The relationship between macrophages and clinicopathological factors, such as survival data, lymph node metastasis, tumoral proliferation, and WHO histological grading are also analyzed. The samples consisted of surgically excised specimens from patients with non-metastatic and metastatic OCSCC and normal oral mucosa (control). Immunohistochemistry, flow cytometry, and qRT-PCR were used to evaluate macrophage populations and the expression of pro- (IL-12, IL-23, and INF-γ) and anti-inflammatory (IL-10 and TGF-β) cytokines. The level required for statistical significance was defined as p<0.05. The data showed a predominance of M2 phenotype (high percentage of IL-10(+)TGF-β(+)) macrophages in the tumor microenvironment of OCSCC. A higher percentage of macrophages expressing TGF-β was seen in the OCSCC group when compared with healthy individuals. The assessment of mRNA expression also presented a greater expression of anti-inflammatory cytokines TGFβ and IL10 in OCSCC when compared with the control group. The percentage of macrophages, demonstrated by immunohistochemistry, was significantly higher in the metastatic OCSCC group than in the non-metastatic and control groups. The log-rank test also showed that the mean survival time for patients with high levels of macrophages was less (44 months) when compared with patients with a low percentage of such cells (93 months). A predominance of the M2 phenotype in the tumor microenvironment of OCSCC could contribute to local immunosuppression, via TGF-β production, and consequently greater lymph node involvement and reduced patient survival time.

Costa NL ，Valadares MC ，Souza PP ，Mendonça EF ，Oliveira JC ，Silva TA ，Batista AC ... -  《-》

Midkine expression in oral squamous cell carcinoma and leukoplakia.

Midkine (MK), a 13-kDa heparin-binding growth factor, is overexpressed in various human cancers. However, its role in the development and progression of oral cavity squamous cell carcinoma (OCSCC) is still unclear. Thus, the aim of this study was to evaluate the expression of MK in samples of OCSCC, leukoplakia, and healthy oral mucosa (control). Surgically excised specimens from patients with primary OCSCC (n = 28) were immunostained for MK, Ki-67, PCNA, p53, bcl-2, Bax, and CD31. Besides this, MK expression was also investigated in leukoplakia and normal oral mucosa. The relationship of MK(+) cells with clinical parameters (tumor location, tumor size, lymph node metastasis, and survival) and microscopic parameters (WHO histological grading, intensity of inflammation, proliferation index, apoptosis, and angiogenesis) was also evaluated. The results showed that MK expression was increased in OCSCC in relation to leukoplakia and normal mucosa. Furthermore, MK expression was increased in late-stage tumors (T3/T4) compared with early-stage lesions (T1/T2). MK-positive lesions also showed increased expression of the anti-apoptotic protein bcl-2. OCSCC, particularly late-stage tumors, exhibits increased MK expression, which may be involved in tumor progression via upregulation of anti-apoptotic genes, as shown by the augmented bcl-2 positivity in MK-positive tumors.

Jham BC ，Costa NL ，Silva JM ，de Miranda AC ，Oliveira JC ，Silva TA ，Batista AC ... -  《-》

Immune response in cervical lymph nodes from patients with primary oral squamous cell carcinoma.

Deficient immune response in the cervical lymph nodes of patients with head and neck squamous cell carcinoma may contribute to dissemination of metastatic neoplastic cells. This study evaluates the immune response in cervical lymph nodes from patients with primary oral cavity squamous cell carcinoma (OCSCC). The density of immature (CD1a(+)) and mature (CD83(+)) dendritic cells (DCs), cytotoxic T lymphocytes CD8(+) /perforin(+) (CTLs), and Foxp3(+) regulatory T (Tregs) cells in the lymph nodes of patients with OCSCC without cervical lymph node metastases (LN1) (negative) (n = 10) were identified through immunohistochemistry. From patients with cervical lymph node metastases, samples were obtained of lymph nodes both with (LM2) (positive) (n = 10) and without (LN2) (negative) (n = 10) metastases. The results demonstrated that the number of CD1a(+) and Foxp3(+) cells was significantly higher in the LM2 group than in either the LN1 or the LN2 group. In addition, the number of CD8(+) /perforin(+) and CD83(+) cells was significantly lower in the LM2 group than in the other groups. The results of this study demonstrate a higher density of immature DCs and Tregs cells and a lower density of mature DCs and activated CTLs in metastatic than in non-metastatic lymph nodes. These findings might indicate an immunosuppressive microenvironment, which could be involved in the spread of neoplastic cells to cervical lymph nodes.

Gonçalves AS ，Costa NL ，Arantes DA ，de Cássia Gonçalves Alencar R ，Silva TA ，Batista AC ... -  《-》

Expression of CD163, interleukin-10, and interferon-gamma in oral squamous cell carcinoma: mutual relationships and prognostic implications.

Tumor-associated macrophages (TAMs) and their associated inflammatory cytokines represent the major inflammatory component of the stroma of many tumors and can affect prognosis in the case of neoplasms. The objective of this study was to determine the prognostic significance of CD163(+) cells, interleukin-10 (IL-10), and interferon-gamma (IFN-γ) in oral lesions associated with oral squamous cell carcinoma (OSCC). The levels of CD163, IFN-γ, and IL-10 in the tissue samples of 240 patients with OSCC and 58 patients with other oral lesions were assessed by immunohistochemistry. Individuals with low IFN-γ levels, high IL-10 levels, and low CD163 levels were of special concern with respect to OSCC progression. We found that high levels of CD163, or a combination of low IFN-γ levels, high IL-10 levels, and low CD163 levels, were associated with poorer overall survival (OS). CD163(+) cells provide better predictive power for OS in comparison with traditional markers, such as clinical stage and lymph node metastasis. Therefore, CD163(+) cells may be effective prognostic predictors of OSCC. IL-10 may also indicate poor outcomes when IFN-γ secretion is low and the cells are CD163(-) .

Wang S ，Sun M ，Gu C ，Wang X ，Chen D ，Zhao E ，Jiao X ，Zheng J ... -  《-》

The clinicopathologic significance of the expression of HLA-G in oral squamous cell carcinoma.

This study aimed to evaluate HLA-G expression in primary oral cavity squamous cell carcinoma (OCSCC) and potentially malignant lesions and to evaluate its relationship with clinicopathologic parameters. HLA-G expression in samples from patients with metastatic and nonmetastatic OCSCC (n = 60), potentially malignant lesions (n = 15), and clinically and histologically normal oral mucosa (n = 10) was characterized by immunohistochemistry. The density of CD8, CD83, and CD68 cells and Ki-67(+) and bcl-2(+) neoplastic cells were analyzed. HLA-G expression by neoplastic cells was significantly higher in metastatic OCSCC compared with nonmetastatic OCSCC (P = .01). Higher HLA-G expression was observed in OCSCC than in potentially malignant lesions (P = .006). Moreover, patients with lower HLA-G expression exhibited a tendency toward longer survival (22 months) compared with those with higher HLA-G expression (16 months). Our findings suggest that increased HLA-G expression in metastatic OCSCC may represent a tumor escape mechanism, which portends an unfavorable clinical prognosis.

Gonçalves AS ，Wastowski IJ ，Capeletti LR ，Sacono NT ，Cortez AP ，Valadares MC ，Silva TA ，Batista AC ... -  《-》