title: Enhanced immunosuppression by therapy-exposed glioblastoma multiforme tumor cells.
abstract: Glioblastoma multiforme (GBM) is a highly malignant brain tumor with an extremely short time to relapse following standard treatment. Since recurrent GBM is often resistant to subsequent radiotherapy and chemotherapy, immunotherapy has been proposed as an alternative treatment option. Although it is well established that GBM induces immune suppression, it is currently unclear what impact prior conventional therapy has on the ability of GBM cells to modulate the immune environment. In this study, we investigated the interaction between immune cells and glioma cells that had been exposed to chemotherapy or irradiation in vitro. We demonstrate that treated glioma cells are more immunosuppressive than untreated cells and form tumors at a faster rate in vivo in an animal model. Cultured supernatant from in vitro-treated primary human GBM cells were also shown to increase suppression, which was independent of accessory suppressor cells or T regulatory cell generation, and could act directly on CD4(+) and CD8(+) T cell proliferation. While a number of key immunosuppressive cytokines were overexpressed in the treated cells, including IL-10, IL-6 and GM-CSF, suppression could be alleviated in a number of treated GBM lines by inhibition of prostaglandin E2. These results reveal for the first time that conventional therapies can alter immunosuppressive pathways in GBM tumor cells, a finding with important implications for the combination of immunotherapy with standard treatment.
authors.affiliation: Vaccine Research Group, Malaghan Institute of Medical Research, Wellington, 6242, New Zealand.
authors.forename: Astrid
authors.initials: A
authors.lastname: Authier
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Farrand
authors.forename: Kate W R
authors.initials: KW
authors.lastname: Broadley
authors.forename: Lindsay R
authors.initials: LR
authors.lastname: Ancelet
authors.forename: Martin K
authors.initials: MK
authors.lastname: Hunn
authors.forename: Sarrabeth
authors.initials: S
authors.lastname: Stone
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: McConnell
authors.forename: Ian F
authors.initials: IF
authors.lastname: Hermans
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D005909:Glioblastoma / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D006801:Humans; D007165:Immunosuppression Therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines
keywords: chemotherapy; glioblastoma multiforme; glioma; immunosuppression; immunotherapy; prostaglandin E2; radiotherapy