P13.10 Chemoattraction of glioma cells in a local hydrogel trap and immune control associated with improved survival and cognitive functions in a mouse model of glioblastoma resection

Abstract

Abstract BACKGROUND Glioblastoma (GB) is the most aggressive brain primary tumor. The prognosis remains poor mainly due to the invasiveness of glioma cells, radio and/or chemoresistance and GB-induced immunosuppressive environment. Here, we propose to use a local delivery system based on a biocompatible hydrogel containing the chemopeptide urotensin II (hUII) or a biased synthetic analog DAB8-hUII, to “trap” GB cells, and/or to control immune cells expressing its G protein-coupled receptor UT, leading to tumor regression and neurological benefit, in a mouse model of GB resection. MATERIAL AND METHODS In vitro, invasion towards UII/analog across different hydrogels or glue of human or murine GB-GFP cell lines was evaluated in Boyden chamber and cloning ring assays. In vivo GB cells were intrastriatally xenografted, then resected while hydrogel- or glue-containing UII/analog was injected in the cavity resection. Behavioral tests, brain immunohistochemical analyses and mouse survival were then investigated. RESULTS In vitro, invasive capacity of human U87 and 42MG or murine GL261 and CT2A GB cells was stimulated by UII loaded into hydrogel-based hyaluronic acid supplemented with collagen or other chemicals, PNIPAAm-PEG, or thrombin-fibrin glue. In vivo, injection of UII- or DAB8-hUII-loaded glue into the cavity resection of GL261 and CT2A GB in C57BL/6 mice significantly improved survival compared with tumor and resected experimental conditions. Neurological status was also tested before and after GB resection. We found that GL261 and CT2A cell-bearing mice expressed altered spontaneous activity, emotion and cognitive functions. Intracavity injection of the glue improved resignation and anxiety and increased motor activity and cognition with a best cognitive recovery with hUII and DAB-8-hUII-loaded glue groups. Ex vivo brain analyses revealed high expression of UT and UII in some GB GFP-positive cells and macrophages within GB core and at the interface with the normal brain, GB cells expressing UT migrating along tortuous podocalyxin+ vascular components. In brains bearing hydrogel/hUII glue, vascularization appears modified and GFAP+ astrocytes and F4/80+ macrophages were highly recruited in the border of the cavity, compared with the other conditions. CONCLUSION A local glue containing UII may trap GB cells and remodel the tumor microenvironment responsible for survival and cognitive improvements, providing new option in the therapeutic arsenal of GB.