Immune infiltration of spontaneous mouse astrocytomas is dominated by immunosuppressive cells from early stages of tumor development

Article Article scientifique Article Immune infiltration of spontaneous mouse astrocytomas is dominated by immunosuppressive cells from early stages of tumor development eng 2010 author Tran Thang Nhu-Nam 637961 author Derouazi Madiha Sabiha 83271 author Philippin Géraldine 516404 author Arcidiaco Séverine 641171 author Besson-Di Berardino Wilma 111390 author Masson Frederick author Hoepner Sabine 691882 author Riccadonna Cristina 703976 author Burkhardt Karim 37488 author Guha Abhijit author Dietrich Pierre-Yves 96532 author Walker Paul Richard 0000-0001-8999-6366 104900 4829-4839 10.1158/0008-5472.CAN-09-3074 20501837 0008-5472 http://cancerres.aacrjournals.org/content/70/12/4829.full.pdf Immune infiltration of advanced human gliomas has been shown, but it is doubtful whether these immune cells affect tumor progression. It could be hypothesized that this infiltrate reflects recently recruited immune cells that are immediately overwhelmed by a high tumor burden. Alternatively, if there is earlier immune detection and infiltration of the tumor, the question arises as to when antitumor competency is lost. To address these issues, we analyzed a transgenic mouse model of spontaneous astrocytoma (GFAP-V(12)HA-ras mice), which allows the study of immune interactions with developing glioma, even at early asymptomatic stages. T cells, including a significant proportion of Tregs, are already present in the brain before symptoms develop, followed later by macrophages, natural killer cells, and dendritic cells. The effector potential of CD8 T-cells is defective, with the absence of granzyme B expression and low expression of IFN-gamma, tumor necrosis factor, and interleukin 2. Overall, our results show an early defective endogenous immune response to gliomas, and local accumulation of immunosuppressive cells at the tumor site. Thus, the antiglioma response is not simply overwhelmed at advanced stages of tumor growth, but is counterbalanced by an inhibitory microenvironment from the outset. Nevertheless, we determined that effector molecule expression (granzyme B, IFN-gamma) by brain-infiltrating CD8 T-cells could be enhanced, despite this unfavorable milieu, by strong immune stimuli. This potential to modulate the strong imbalance in local antiglioma immunity is encouraging for the development and optimization of future glioma immunotherapies. Animals Astrocytoma/*immunology/pathology Brain Neoplasms/*immunology/pathology CD8-Positive T-Lymphocytes/immunology Cell Movement Flow Cytometry Glial Fibrillary Acidic Protein/metabolism Granzymes/metabolism Humans Immunoenzyme Techniques Immunosuppression Lymphocyte Activation Lymphocytes, Tumor-Infiltrating/*immunology Mice Mice, Transgenic Proto-Oncogene Proteins p21(ras)/physiology T-Lymphocytes, Regulatory/*immunology Dewey 616 56 Département de médecine 221 false 401 Immunobiologie des tumeurs du cerveau 669 27 Immunothérapie des cancers 42 Cancer research 70 12 72878ebb-afe9-425f-b972-a81e19718de5 Article Restricted file1.pdf 675467 application/pdf restrictedAccess Faculté de médecine / Section de médecine clinique / Département de médecine

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Immune infiltration of spontaneous mouse astrocytomas is dominated by immunosuppressive cells from early stages of tumor development	Cancer research			2010	627	3

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