PO-265 Cisplatin induces pro-inflammatory program and modulates pro-angiogenic potential of human tumor-associated macrophages

Abstract

IntroductionChemotherapy is one of the main methods of antitumor treatment. The effect of chemotherapy depends not only on the cytotoxicity for cancer cells, but also on the response of immune component of tumour microenvironment. Key innate immune cells in tumour microenvironment are tumor-associated macrophages (TAM), that can cooperate or interfere with anti-cancer therapies.The aim of our study was to analyse how commonly used chemotherapeutic agent cisplatin affects major function of TAM that control tumour progression.Material and methodsHuman primary monocytes-derived macrophages were stimulated ex vivo by supernatants of breast cancer cells MCF-7 and colorectal cancer cells Colo206F to model cancer-specific TAM. Cisplatin treatment was performed on day 6 of macrophages differentiation. Confocal microscopy was used for the analysis of surface macrophage receptors. RT-PCR and ELISA were used to analyse production of secreted pro-inflammatory and pro-angiogenic cytokines markers.Results and discussionsIn the model breast and colon cancer-specific TAM we identified both stimulating and suppressing effects of cisplatin. The major stimulating effects were identified on the expression of pro-inflammatory cytokines IL1b, IL6, IL8, TNFa, anti-inflammatory cytokine IL10, TGFb and major pro-angiogenic factor VEGF-A. Cisplatin suppressed the expression of scavenger receptors CD163, CD206, as well as chitinase-like proteins YKL-39 and YKL-40, that support tumor-angiogenesis. Cisplatin did not significantly affect the expression of matrix metalloproteinases. ELISA demonstrated that significant levels of secreted VEGF are produced only by breast cancer TAM, and are enhanced by cisplatin treatment. Confocal microscopy analysis demonstrated the suppressive effect of cisplatin on the expression of receptors responsible for the internalisation of components of the tumour microenvironment: CD206, stabilin-1 and CD163 in both breast and colon cancer TAM. Cispalin treatment slightly enhanced expression of LYVE1 in breast cancer TAM, but not in colon cancer TAM.ConclusionWe found that cisplatin has a stimulating effects on the mixed pro-inflammatory program of TAM, and enhanced expression of major pro-angiogenic factor VEGF therefore creating supportive conditions for the enhanced mutagenesis of transformed cells and enhanced metastasis. Out data indicate that additional targeting of TAM during the chemotherapy course is a promising therapeutic strategy to avoid cancer metastasis.This study was supported by grand RNF №14-15-00350.