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CCR7-expressing B16 melanoma cells downregulate interferon-?-mediated inflammation and increase lymphangiogenesis in the tumor microenvironment.

ABSTRACT: The expression of the CC chemokine receptor-7 (CCR7) by cancers, including melanoma, augments lymph node (LN) metastasis, but little is known about its role in lymphangiogenesis and anti-tumor immunity. We injected control B16 murine melanoma cells (pLNCX2-B16) and CCR7-overexpressing B16 cells (CCR7-B16) in murine footpads and compared resulting tumors at the protein and mRNA level using immunostaining, Affymetrix gene microarray and quantitative reverse-transcriptase PCR. Although control and CCR7-B16 primary tumors were of similar size, LN metastasis was dramatically enhanced in CCR7-B16 tumors. Microarray analysis of leukocyte-depleted pLNCX2-B16 and CCR7-B16 tumor cell suspensions showed that three major groups of genes linked to interferon (IFN)-? signaling pathways (for example, STAT1, CXCR 9-11, CCL5 and CXCL10, major histocompatibility complex (MHC) I and MHC II) were downregulated in the CCR7-B16 tumor microenvironment, suggesting activation through CCR7 can downregulate pathways critical for host anti-tumor immunity. In addition, mRNA expression of the lymphatic marker podoplanin was upregulated in CCR7-B16 tumors by 3.35-fold versus control tumors. Anti-podoplanin monoclonal antibody staining revealed a three-fold increase in intratumoral CCL21-expressing lymphatic vessels, as well as a two-fold increase in the number of invading tumor cells per lymphatic vessel in CCR7-B16 versus control tumors. Enhanced anti-vascular endothelial growth factor C (VEGF-C) staining was present in CCR7-B16 versus control tumors, suggesting that VEGF-C may have a role in the CCR7-mediated lymphangiogenesis. In summary, CCR7-B16 tumors show a striking decrease in IFN-?-mediated inflammatory gene expression in contrast to increased expression of VEGF-C, CCL21 and podoplanin by lymphatic vessels. Enhanced lymphangiogenesis may contribute to the dramatic increase in LN metastasis that is observed in the CCR7-expressing tumors.

SUBMITTER: Takekoshi T

PROVIDER: S-EPMC3412639 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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CCR7-expressing B16 melanoma cells downregulate interferon-γ-mediated inflammation and increase lymphangiogenesis in the tumor microenvironment.

Takekoshi T T Fang L L Paragh G G Hwang S T ST

Oncogenesis 20120507

The expression of the CC chemokine receptor-7 (CCR7) by cancers, including melanoma, augments lymph node (LN) metastasis, but little is known about its role in lymphangiogenesis and anti-tumor immunity. We injected control B16 murine melanoma cells (pLNCX2-B16) and CCR7-overexpressing B16 cells (CCR7-B16) in murine footpads and compared resulting tumors at the protein and mRNA level using immunostaining, Affymetrix gene microarray and quantitative reverse-transcriptase PCR. Although control and ...[more]

PMID: 23552640

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Project description:Alphavirus vectors are promising tools for cancer treatment. However, relevant entry mechanisms and interactions with host cells are still not clearly understood. The first step toward a more effective therapy is the identification of novel intracellular alterations that could be associated with cancer aggressiveness and could affect the therapeutic potential of these vectors. In this study, we observed that alphaviruses efficiently infected B16 mouse melanoma tumors/tumor cells in vivo, whereas their transduction efficiency in B16 cells under in vitro conditions was blocked. Therefore, we further aimed to understand the mechanisms pertaining to the differential transduction efficacy of alphaviruses in B16 tumor cells under varying growth conditions. We hypothesized that the tumor microenvironment might alter gene expression in B16 cells, leading to an up-regulation of the expression of virus-binding receptors or factors associated with virus entry and replication. To test our hypothesis, we performed a proteomics analysis of B16 cells cultured in vitro and of B16 cells isolated from tumors, and we identified 277 differentially regulated proteins. A further in-depth analysis to identify the biological and molecular functions of the detected proteins revealed a set of candidate genes that could affect virus infectivity. Importantly, we observed a decrease in the expression of interferon ? (IFN-?) in tumor-isolated cells that resulted in the suppression of several IFN-regulated genes, thereby abrogating host cell antiviral defense. Additionally, differences in the expression of genes that regulate cytoskeletal organization caused significant alterations in cell membrane elasticity. Taken together, our findings demonstrated favorable intracellular conditions for alphavirus transduction/replication that occurred during tumor transformation. These results pave the way for optimizing the development of strategies for the application of alphaviral vectors as a potent cancer therapy.

Project description:BackgroundTuberculosis screening in psoriasis patients is complex due to the immunological alterations associated with psoriasis, the presence of comorbidities, and the effect of immunosuppressive treatment. However, it is not established whether the results of screening tests are affected by these factors in psoriasis patients.ObjectivesTo determine whether there is a change in the results of the tuberculin skin test (TST) or the interferon-gamma release assay (IGRA) in psoriasis patients living in tuberculosis (TB)-endemic area after 12 weeks of methotrexate (MTX) treatment and to investigate the association of the test results with clinical and inflammatory markers.MethodsForty-five patients were selected for a prospective single-arm self-controlled study and followed for at least 18 months. The TST, IGRA, Psoriasis Area and Severity Index (PASI), and inflammatory factors (erythrocyte sedimentation rate (ESR), C-reactive protein, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha levels), were determined before and after 12 weeks of oral 15 mg per week MTX administration and compared. The associations between the IGRA and TST results were verified before and after treatment according to inflammatory factors and clinical characteristics (age, blood glucose, weight, body mass index, disease duration, and PASI).ResultsWe collected data on 25 patients who completed the full course of therapy and the follow-up. None of the patients developed TB. TST positivity was significantly elevated at week 12 (25% baseline vs 44% at week 12, P < 0.037). Three IGRAs followed the TST conversions. There was no difference between TST and IGRA pre- or posttreatment. Serum IFN-γ increased significantly in week 12 (15.95 pg/ml baseline vs 18.82 pg/ml at week 12, P < 0.005) and tended to be higher among TST-positive patients (P = 0.072). The baseline IGRA was associated with a higher ESR (P = 0.038). None of the test results were associated with clinical characteristics.ConclusionsIn addition to the classic booster effect, TST conversions in patients using MTX can occur due to an increase in IFN-γ. However, it is not possible to exclude true TST conversions. Therefore, other diagnostic methods, like IGRA or chest tomography, should be used when the TST has intermediate results.

Dataset Information

CCR7-expressing B16 melanoma cells downregulate interferon-?-mediated inflammation and increase lymphangiogenesis in the tumor microenvironment.

Publications

CCR7-expressing B16 melanoma cells downregulate interferon-γ-mediated inflammation and increase lymphangiogenesis in the tumor microenvironment.

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