Endostatin gene therapy inhibits intratumoral macrophage M2 polarization

Author(s)

Foguer, Karen ^{[1, 2]} ; Braga, Marina de Souza ^{[1, 2]} ; Schatzmann Peron, Jean Pierre ^[3] ; Bortoluci, Karina Ramalho ^[4] ; Bellini, Maria Helena ^{[1, 2]}

Affiliation

^[1] Univ Fed Sao Paulo, Div Nephrol, Sao Paulo - Brazil

^[2] IPEN CNEN, Dept Biotechnol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo - Brazil

^[4] Univ Fed Sao Paulo, Dept Biol Biol Sci, Sao Paulo - Brazil

• Document type: Journal article
• Source: BIOMEDICINE & PHARMACOTHERAPY; v. 79, p. 102-111, APR 2016.
• Web of Science Citations: 3

Abstract

Background: Renal cell carcinoma (RCC) is a highly vascularized cancer resistant to chemotherapy and radiotherapy. RCC is frequently infiltrated with immune cells, with macrophages being the most abundant cell type. Alternatively activated M2 macrophages are known to contribute to tumor progression. Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. In this study, we investigated the impact of ES gene therapy on the polarization of tumor-associated macrophages (TAMs) in lung metastases from tumor-bearing mice. Methods: BALB/c mice divided into three groups: Normal, Control and ES-treated. Tumor-bearing mice were treated with ES-transduced cells or control cells over ten days. At the end of the study, plasma was collected, and pulmonary macrophages were isolated and used for FACS or RT-PCR. ELISA tests were used to analyze plasma and cell culture supernatant cytokines. Results: ES treatment significantly reduced the levels of anti-inflammatory and pro-angiogenic cytokines, including IL4, IL-10, IL-13 and VEGF. Gene expression of M2 markers, such as IL-10, Arg-1, VEGF and YM-1, declined significantly. Flow cytometry showed a reduction in the number of M2 F4/80 + CD36 + CD206 + CD209+ macrophages and in IL-10 secretion by these cells. Reduced levels of IL-10 were also found in the culture supernatants of the ES-treated group. Conclusions: Our research corroborates previous observations that ES has an important anti-tumoral role. However, aside from promoting interferon-g secretion and an effective T cell response, we show here that this switch is extended to TAMs, complicating the maintenance of pro-tumorigenic M2 macrophages and thus favoring tumor elimination. (C) 2016 Elsevier Masson SAS. All rights reserved. (AU)

• FAPESP's process: 11/18703-2 - The role of Indoleamine-2,3-dioxigenase and the Triptophan - Kynurenines axis through NMDA receptors over the immune response in the EAE and stroke model
• Grantee: Jean Pierre Schatzmann Peron
• Support Opportunities: Research Grants - Young Investigators Grants