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Purpose Improvements of heat-delivery systems have led to hyperthermia (HT) being increasingly recognized as an adjunct treatment modality also for brain tumors. But how HT affects the immune phenotype of glioblastoma cells is only scarcely known.Materials and Methods We therefore investigated the effect of in vitro HT, radiotherapy (RT), and the combination of both (RHT) on cell death modalities, immune checkpoint molecule (ICM) expression and release of the danger signal HSP70 of two human glioblastoma cell lines (U87 and U251) by using multicolor flow cytometry and ELISA. Hyperthermia was performed once or twice for 60-minute sessions reaching temperatures of 39 °C, 41 °C, and 44 °C, respectively. RT was administered with 5 x 2 Gy. Results A hyperthermia chamber for cell culture t-flasks regulating the temperature via a contact sensor was developed. While the glioblastoma cells were rather radioresistant, particularly in U251 cells, the combination of RT with HT significantly increased the percentage of apoptotic and necrotic cells for all temperatures examined and for both, single and double HT application. In line with that, an increased release of HSP 70 was seen only in U251 cells, mainly following treatment with HT at temperatures of 44 °C alone or in combination with RT. In contrast, immune suppressive (PD-L1, PD-L2, HVEM) and immune stimulatory (ICOS-L, CD137-L and Ox40-L) ICMs were significantly increased mostly on U87 cells, and particularly after RHT with 41 °C.Conclusions Individual assessment of the glioblastoma immune cell phenotype with regard to the planned treatment is mandatory to optimize multimodal radio-immunotherapy protocols including HT.

Purpose: Improvements of heat-delivery systems have led to hyperthermia (HT) being increasingly recognized as an adjunct treatment modality also for brain tumors. But how HT affects the immune phenotype of glioblastoma cells is only scarcely known. Materials and Methods: We therefore investigated the effect of in vitro HT, radiotherapy (RT), and the combination of both (RHT) on cell death modalities, immune checkpoint molecule (ICM) expression and release of the danger signal HSP70 of two human glioblastoma cell lines (U87 and U251) by using multicolor flow cytometry and ELISA. Hyperthermia was performed once or twice for 60-minute sessions reaching temperatures of 39 oC, 41 oC, and 44 oC, respectively. RT was administered with 5 x 2 Gy. Results: A hyperthermia chamber for cell culture t-flasks regulating the temperature via a contact sensor was developed. While the glioblastoma cells were rather radioresistant, particularly in U251 cells, the combination of RT with HT significantly increased the percentage of apoptotic and necrotic cells for all temperatures examined and for both, single and double HT application. In line with that, an increased release of HSP 70 was seen only in U251 cells, mainly following treatment with HT at temperatures of 44 oC alone or in combination with RT. In contrast, immune suppressive (PD-L1, PD-L2, HVEM) and immune stimulatory (ICOS-L, CD137-L and Ox40-L) ICMs were significantly increased mostly on U87 cells, and particularly after RHT with 41 oC. Conclusions: Individual assessment of the glioblastoma immune cell phenotype with regard to the planned treatment is mandatory to optimize multimodal radio-immunotherapy protocols including HT. [ABSTRACT FROM AUTHOR]

A conceptually new bimodal immunoradiotherapy treatment was demonstrated using thermoresponsive polymer β-glucan- graft -poly(2-isopropyl-2-oxazoline- co -2-butyl-2-oxazoline) bearing complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid with yttrium-90(III) at the graft ends. The behavior of this thermoresponsive polymer in aqueous solutions was studied, and it showed the appropriate cloud point temperature for brachytherapy applications. The polymer was tested in vitro , and it exhibited nontoxicity and active uptake into cancer cells and macrophages with colocalization in the lysosomes and macrophagosomes. Moreover, the observed oxidative burst response of the leukocytes established the immunostimulatory properties of the polymer, which were also studied in vivo after injection into the thigh muscles of healthy mice. The subsequent histological evaluation revealed the extensive immune activation reactions at the site of injection. Furthermore, the production of tumor necrosis factor α induced by the prepared polymer was observed in vitro , denoting the optimistic prognosis of the treatment. The biodistribution study in vivo indicated the formation of the polymer depot, which was gradually degraded and excluded from the body. The radiolabeled polymer was used during in vivo antitumor efficiency experiments on mice with EL4 lymphoma. The immunoradiotherapy group (treated with the radiolabeled polymer) demonstrated the complete inhibition of tumor growth during the beginning of the treatment. Moreover, 7 of the 15 mice were completely cured in this group, while the others exhibited significantly prolonged survival time compared to the control group. The in vivo experiments indicated the considerable synergistic effect of using immunoradiotherapy compared to separately using immunotherapy or radiotherapy. [ABSTRACT FROM AUTHOR]