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- ItemGas Plasma Exposure of Glioblastoma Is Cytotoxic and Immunomodulatory in Patient-Derived GBM Tissue(Basel : MDPI, 2022) Bekeschus, Sander; Ispirjan, Mikael; Freund, Eric; Kinnen, Frederik; Moritz, Juliane; Saadati, Fariba; Eckroth, Jacqueline; Singer, Debora; Stope, Matthias B.; Wende, Kristian; Ritter, Christoph A.; Schroeder, Henry W. S.; Marx, SaschaGlioblastoma multiforme (GBM) is the most common primary malignant adult brain tumor. Therapeutic options for glioblastoma are maximal surgical resection, chemotherapy, and radiotherapy. Therapy resistance and tumor recurrence demand, however, new strategies. Several experimental studies have suggested gas plasma technology, a partially ionized gas that generates a potent mixture of reactive oxygen species (ROS), as a future complement to the existing treatment arsenal. However, aspects such as immunomodulation, inflammatory consequences, and feasibility studies using GBM tissue have not been addressed so far. In vitro, gas plasma generated ROS that oxidized cells and led to a treatment time-dependent metabolic activity decline and G2 cell cycle arrest. In addition, peripheral blood-derived monocytes were co-cultured with glioblastoma cells, and immunomodulatory surface expression markers and cytokine release were screened. Gas plasma treatment of either cell type, for instance, decreased the expression of the M2-macrophage marker CD163 and the tolerogenic molecule SIGLEC1 (CD169). In patient-derived GBM tissue samples exposed to the plasma jet kINPen ex vivo, apoptosis was significantly increased. Quantitative chemokine/cytokine release screening revealed gas plasma exposure to significantly decrease 5 out of 11 tested chemokines and cytokines, namely IL-6, TGF-β, sTREM-2, b-NGF, and TNF-α involved in GBM apoptosis and immunomodulation. In summary, the immuno-modulatory and proapoptotic action shown in this study might be an important step forward to first clinical observational studies on the future discovery of gas plasma technology’s potential in neurosurgery and neuro-oncology especially in putative adjuvant or combinatory GBM treatment settings.
- ItemDevitalization of Glioblastoma Cancer Cells by Non-invasive Physical Plasma: Modulation of Proliferative Signalling Cascades(Attiki : [Verlag nicht ermittelbar], 2022) Lehmann, Sebastian; Bien-Möller, Sandra; Marx, Sascha; Bekeschus, Sander; Schroeder, Henry W.S.; Mustea, Alexander; Stope, Matthias B.Background/Aim: Glioblastoma (GBM) is the most common and most lethal type of cancer of the central nervous system in adults. Despite aggressive treatment, which is based on surgical resection, if possible, followed by radiation and chemotherapy, a high recurrence rate and therapy resistance is observed. Thus, additional innovative therapies are urgently needed to improve the poor median survival of only 15 months. Treatment of solid tumours with non-invasive physical plasma (NIPP) represents such a novel and innovative anticancer procedure. Materials and Methods: In this study, we investigated the effect of NIPP, an ionized argon gas, on the in vitro growth of human GBM cell lines, LN-18 and U-87 MG. Proliferation was measured by live cell count. Subsequently, proliferative factors were analysed at the level of nucleic acids (polymerase chain reaction) and proteins (western blotting). Results: For both GBM lines, a treatment time-dependent decrease in growth was observed compared to controls. Additionally, NIPP treatment resulted in reduced rates of AKT serine/threonine kinase 1 (AKT1) and extracellular-regulated kinase 1/2 ERK1/2 expression, whereas expression of p21, proliferating cell nuclear antigen, and heat-shock proteins 90α and 90β was not affected. In both cell lines, a strong increase in expression of tumour-suppressive microRNA-1 (miR-1) was detected after exposure to NIPP. Conclusion: Our results demonstrated that NIPP is able to efficiently attenuate growth of GBM cells and suggest AKT1, ERK1/2 and miR-1 to be pivotal factors of NIPP-modulated cellular signalling. Translated into the clinical setting, NIPP may represent a promising option for the treatment of GBM.
- ItemImmunophenotyping of Circulating and Intratumoral Myeloid and T Cells in Glioblastoma Patients(Basel : MDPI, 2022) Marx, Sascha; Wilken, Fabian; Miebach, Lea; Ispirjan, Mikael; Kinnen, Frederik; Paul, Sebastian; Bien-Möller, Sandra; Freund, Eric; Baldauf, Jörg; Fleck, Steffen; Siebert, Nikolai; Lode, Holger; Stahl, Andreas; Rauch, Bernhard H.; Singer, Stephan; Ritter, Christoph; Schroeder, Henry W. S.; Bekeschus, SanderGlioblastoma is the most common and lethal primary brain malignancy that almost inevitably recurs as therapy-refractory cancer. While the success of immune checkpoint blockade (ICB) revealed the immense potential of immune-targeted therapies in several types of cancers outside the central nervous system, it failed to show objective responses in glioblastoma patients as of now. The ability of glioblastoma cells to drive multiple modes of T cell dysfunction while exhibiting low-quality neoepitopes, low-mutational load, and poor antigen priming limits anti-tumor immunity and efficacy of antigen-unspecific immunotherapies such as ICB. An in-depth understanding of the GBM immune landscape is essential to delineate and reprogram such immunosuppressive circuits during disease progression. In this view, the present study aimed to characterize the peripheral and intratumoral immune compartments of 35 glioblastoma patients compared to age- and sex-matched healthy control probands, particularly focusing on exhaustion signatures on myeloid and T cell subsets. Compared to healthy control participants, different immune signatures were already found in the peripheral circulation, partially related to the steroid medication the patients received. Intratumoral CD4+ and CD8+ TEM cells (CD62Llow/CD45ROhigh) revealed a high expression of PD1, which was also increased on intratumoral, pro-tumorigenic macrophages/microglia. Histopathological analysis further identified high PSGL-1 expression levels of the latter, which has recently been linked to increased metastasis in melanoma and colon cancer via P-selectin-mediated platelet activation. Overall, the present study comprises immunophenotyping of a patient cohort to give implications for eligible immunotherapeutic targets in neurooncology in the future.