Shekarian Tala, Zinner Carl P, Bartoszek Ewelina M, Duchemin Wandrille, Wachnowicz Anna T, Hogan Sabrina, Etter Manina M, Flammer Julia, Paganetti Chiara, Martins Tomas A, Schmassmann Philip, Zanganeh Steven, Le Goff Francois, Muraro Manuele G, Ritz Marie-Françoise, Phillips Darci, Bhate Salil S, Barlow Graham L, Nolan Garry P, Schürch Christian M, Hutter Gregor
Brain Tumor Immunotherapy Lab, Department of Biomedicine, University of Basel, Basel, Switzerland.
Institute of Medical Genetics and Pathology, University Hospital and University of Basel, Basel, Switzerland.
Sci Adv. 2022 Jul;8(26):eabn9440. doi: 10.1126/sciadv.abn9440. Epub 2022 Jul 1.
A patient-tailored, ex vivo drug response platform for glioblastoma (GBM) would facilitate therapy planning, provide insights into treatment-induced mechanisms in the immune tumor microenvironment (iTME), and enable the discovery of biomarkers of response. We cultured regionally annotated GBM explants in perfusion bioreactors to assess iTME responses to immunotherapy. Explants were treated with anti-CD47, anti-PD-1, or their combination, and analyzed by multiplexed microscopy [CO-Detection by indEXing (CODEX)], enabling the spatially resolved identification of >850,000 single cells, accompanied by explant secretome interrogation. Center and periphery explants differed in their cell type and soluble factor composition, and responses to immunotherapy. A subset of explants displayed increased interferon-γ levels, which correlated with shifts in immune cell composition within specified tissue compartments. Our study demonstrates that ex vivo immunotherapy of GBM explants enables an active antitumoral immune response within the tumor center and provides a framework for multidimensional personalized assessment of tumor response to immunotherapy.
一个针对胶质母细胞瘤（GBM）的患者定制的体外药物反应平台将有助于治疗规划，深入了解免疫肿瘤微环境（iTME）中治疗诱导的机制，并能够发现反应生物标志物。我们在灌注生物反应器中培养区域注释的GBM外植体，以评估iTME对免疫疗法的反应。外植体用抗CD47、抗PD-1或其组合进行处理，并通过多重显微镜[索引编码检测（CODEX）]进行分析，能够在空间上解析识别超过850,000个单细胞，同时对外植体分泌组进行检测。中心和外周外植体在细胞类型、可溶性因子组成以及对免疫疗法的反应方面存在差异。一部分外植体显示出干扰素-γ水平升高，这与特定组织隔室内免疫细胞组成的变化相关。我们的研究表明，GBM外植体的体外免疫疗法能够在肿瘤中心引发积极的抗肿瘤免疫反应，并为肿瘤对免疫疗法反应的多维度个性化评估提供了一个框架。
