A lovastatin-elicited genetic program inhibits M2 macrophage polarization and enhances T cell infiltration into spontaneous mouse mammary tumors

// Emilia Mira 1 , Lorena Carmona-Rodriguez 1 , Manuel Tardaguila 1 , Inigo Azcoitia 2 , Alicia Gonzalez-Martin 1,4 , Luis Almonacid 1 , Josefina Casas 3 , Gemma Fabrias 3 , Santos Manes 1 1 Department of Immunology and Oncology, Centro Nacional de Biotecnologia/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 Correspondence: Santos Manes, 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 Abstract 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.