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 1 and CD8 1 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.Despite aggressive upfront therapy for glioblastoma multiforme (GBM), which includes surgical resection, radiotherapy and temozolomide-based chemotherapy, the median time to recurrence is only 6.9 months after standard treatment.1

Immune phenotypes predict survival in patients with glioblastoma multiforme

“…When the CD3-expression density is significantly diminished in patients compared to healthy donors, this indicates impaired responsiveness by TCR-mediated activation. In addition, the expression of the TCRα/β complex was also different between the GBM patients and controls, a fact which may be related to immune suppression by a higher proportion of immune regulatory elements [6] including cytokines, such as IL-10 [18, 19]. …”

Cyclooxygenase-2 in glioblastoma multiforme

“…Both chemotherapy and radiotherapy can induce COX-2 to synthesize PGE 2 in GBM cells to cause overexpression of immunosuppressive cytokines, such as interleukin 6 (IL-6), IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF), and to block T cell infiltration and proliferation. The conventional treatment-induced immunosuppression can be alleviated by the nonselective COX inhibitor diclofenac [69]. Likewise, incubation with the COX-2 inhibitor NS398 before but not after radiotherapy enhanced radiation-induced human GBM cell death [70]; celecoxib increased the radiosensitivity of GBM cells and, thus, reduced the clonogenic survival of irradiated cells [71].…”

“…All these setbacks together make it unlikely that chronic COX-2 inhibition alone is a sustainable therapeutic strategy, even though short-term exposure might provide some benefits. However, COX-2 inhibitors should be considered as adjunct treatment owing to their effect on sensitization of GBM to traditional chemotherapy and radiotherapy [64–66,69–71,75]. In addition, nanocapsules could offer more-efficient strategies to deliver COX inhibitors to gliomas, as recent studies showed that nanocapsules increased the intratumoral bioavailability of indomethacin and enhanced its inhibition of the growth of implanted gliomas [6,57,96].…”

Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin

“…65 Both radiation and temozolomide act upon GB cells themselves to potentiate their innate immunosuppressive properties. 66 Supernatants from primary GB cells exposed transiently to fractionated radiation were immunosuppressive to untreated lymphocytes. These supernates of radiation-exposed glioma cells contained increased levels of many cytokines including G-CSF.…”

“…These supernates of radiation-exposed glioma cells contained increased levels of many cytokines including G-CSF. 66 In the homeostatic rest state, immature myeloid cells in BM differentiate into the mature granulocytes and monocytes circulating in blood. During infection, cancer, and other homeostatic disruptions, immature myeloid cells can also differentiate into myeloid-derived suppressor cells (MDSCs).…”