title: Immune infiltration of spontaneous mouse astrocytomas is dominated by immunosuppressive cells from early stages of tumor development.
abstract: 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.
authors.affiliation: Center of Oncology, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Nhu Nam
authors.initials: NN
authors.lastname: Tran Thang
authors.forename: Madiha
authors.initials: M
authors.lastname: Derouazi
authors.forename: Géraldine
authors.initials: G
authors.lastname: Philippin
authors.forename: Séverine
authors.initials: S
authors.lastname: Arcidiaco
authors.forename: Wilma
authors.initials: W
authors.lastname: Di Berardino-Besson
authors.forename: Frédérick
authors.initials: F
authors.lastname: Masson
authors.forename: Sabine
authors.initials: S
authors.lastname: Hoepner
authors.forename: Cristina
authors.initials: C
authors.lastname: Riccadonna
authors.forename: Karim
authors.initials: K
authors.lastname: Burkhardt
authors.forename: Abhijit
authors.initials: A
authors.lastname: Guha
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Dietrich
authors.forename: Paul R
authors.initials: PR
authors.lastname: Walker
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000276:immunology* / Q000473:pathology; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement; D005434:Flow Cytometry; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D053804:Granzymes; C509214:Gzmb protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)