Toll-Like Receptor 7 Agonist Therapy with Imidazoquinoline Enhances Cancer Cell Death and Increases Lymphocytic Infiltration and Proinflammatory Cytokine Production in Established Tumors of a Renal Cell Carcinoma Mouse ModelReport as inadecuate




Toll-Like Receptor 7 Agonist Therapy with Imidazoquinoline Enhances Cancer Cell Death and Increases Lymphocytic Infiltration and Proinflammatory Cytokine Production in Established Tumors of a Renal Cell Carcinoma Mouse Model - Download this document for free, or read online. Document in PDF available to download.

Journal of Oncology - Volume 2012 2012, Article ID 103298, 11 pages -

Research Article

Department of Urology, Weill Medical College of Cornell University, New York, NY 10065, USA

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

Smith Institute of Urology, North Shore-Long Island Jewish Health System, New Hyde Park, NY 11042, USA

Received 1 October 2011; Accepted 14 November 2011

Academic Editor: Dirk Rades

Copyright © 2012 Eric C. Kauffman et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Imidazoquinolines are synthetic toll-like receptor 7 and 8 agonists and potent dendritic cell activators with established anticancer activity. Here we test the hypothesis that imidazoquinoline has in vivo efficacy within established renal cell carcinoma RCC tumors. Immunocompetent mice bearing syngeneic RCC xenografts were treated with imidazoquinoline or placebo at two separate time points. Harvested tumors were assayed by TUNEL-caspase-3-Ki67 immunostains to evaluate cell death-apoptosis-proliferation, and CD3-B220-CD45 immunostains to evaluate T-cell lymphocyte-B-cell lymphocyte-pan-leukocyte tumor infiltration. ELISA measurement of tumor and serum levels of proinflammatory cytokines, IL-6 and MCP-1, was performed. A single imidazoquinoline dose significantly decreased RCC tumor growth by 50% and repeat dosing compounded the effect, without observed weight loss or other toxicity. Tumor immunostaining revealed significant increases in cell death and apoptosis without changes in cell proliferation, supporting induction of apoptosis as the primary mechanism of tumor growth suppression. Imidazoquinoline treatment also significantly enhanced peritumoral aggregation and intratumoral infiltration by T-cell lymphocytes, while increasing intratumoral but not serum levels of proinflammatory cytokines. In conclusion, imidazoquinoline treatment enhances T-cell lymphocyte infiltration and proinflammatory cytokine production within established mouse RCC tumors, while suppressing tumor growth via induction of cancer cell apoptosis. These findings support a therapeutic role for imidazoquinoline in RCC.





Author: Eric C. Kauffman, Huixian Liu, Michael J. Schwartz, and Douglas S. Scherr

Source: https://www.hindawi.com/



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