A lovastatin-elicited genetic program inhibits M2 macrophage polarization and enhances T cell infiltration into spontaneous mouse mammary tumors
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Emilia Mira1, Lorena Carmona-Rodríguez1, Manuel Tardáguila1, Iñigo Azcoitia2, Alicia González-Martín1,4, Luis Almonacid1, Josefina Casas3, Gemma Fabriás3, Santos Mañes1
1 Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain,
2 Department of Cell Biology, School of Biology, Universidad Complutense de Madrid, Madrid, Spain,
3 Department of Biomedicinal Chemistry, Catalan Institute of Advanced Chemistry/CSIC, Barcelona, Spain
4 Present address: The Scripps Research Institute, Department of Immunology and Microbial Science, La Jolla, CA
Santos Mañes, email:
Emilia Mira, email:
Keywords: inflammation, tumor immunity, macrophage polarization, angiogenesis, vascular normalization, myeloid infiltration, lymphoid infiltration, statins
Received: September 05, 2013 Accepted: October 24, 2013 Published: October 26, 2013
Beyond their ability to inhibit cholesterol biosynthesis, the statins have pleiotropic effects that include anti-inflammatory and immunomodulatory activities. Statins could have clinical utility, alone or in combination with other chemotherapeutics, in the treatment of cancer. The mechanisms that underlie the anti-tumor activity of the statins are nonetheless poorly defined. No studies have analyzed how they alter the tumor-associated leukocyte infiltrate, a central factor that influences tumor stroma and cancer evolution. Here we used HER2/neu transgenic (Tg-neu) mice to analyze the effect of lovastatin (Lov) on the inflammatory reaction of spontaneous mammary tumors. Lov treatment of tumor-bearing Tg-neu mice did not alter growth of established tumors, but significantly reduced the number of new oncogenic lesions in these mice. Moreover, Lov inhibited the growth of newly implanted Tg-neu tumors in immunocompetent but not in immunodeficient mice. We found that Lov enhanced tumor infiltration by effector T cells, and reduced the number of immunosuppressive and pro-angiogenic M2-like tumor-associated macrophages (TAM). Concomitantly, the drug improved the structure and function of the tumor vasculature, measured as enhanced tumor oxygenation and penetration of cytotoxic drugs. Microarray analysis identified a Lov-elicited genetic program in Tg-neu tumors that might explain these effects; we observed Lov-induced downregulation of placental growth factor, which triggers aberrant angiogenesis and M2-like TAM polarization. Our results identify a role for lovastatin in the shaping and re-education of the inflammatory infiltrate in tumors, with functional consequences in angiogenesis and antitumor immunity.
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