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Immunotherapy of glioblastoma explants induces interferon-γ responses and spatial immune cell rearrangements in tumor center, but not periphery.

ABSTRACT: 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.

SUBMITTER: Shekarian T

PROVIDER: S-EPMC10883360 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Immunotherapy of glioblastoma explants induces interferon-γ responses and spatial immune cell rearrangements in tumor center, but not periphery.

Shekarian Tala T Zinner Carl P CP Bartoszek Ewelina M EM Duchemin Wandrille W Wachnowicz Anna T AT Hogan Sabrina S Etter Manina M MM Flammer Julia J Paganetti Chiara C Martins Tomas A TA Schmassmann Philip P Zanganeh Steven S Le Goff Francois F Muraro Manuele G MG Ritz Marie-Françoise MF Phillips Darci D Bhate Salil S SS Barlow Graham L GL Nolan Garry P GP Schürch Christian M CM Hutter Gregor G

Science advances 20220701 26

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 in ...[more]

PMID: 35776791

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Project description:Prolonged interferon-γ signaling activation induces cancer resistance to therapeutics, especially immunotherapy. However, the detailed mechanisms are not well characterized. In present study, we explored cancer intrinsic resistant mechanisms employing for evading immune checkpoint blockade (ICB) and searched for key immune checkpoints contributing to the constitution of suppressive immune microenvironment of glioblastoma (GBM). We screened key immune checkpoint (IC) associated with IFN signaling activation in GBM according to integrated transcriptomic profiling on the ICs. Expression analysis and functional assays revealed that malignant cells elevated the key IC, TNFRSF14 expression under IFN-γ stimulation, which enhanced their proliferation and in vivo tumorigenicity. Therapeutic efficiency of TNFRSF14 disruption in GBM was evaluated with in vitro and in vivo functional assays, including immunofluorescence, transwell, RT-qPCR, flow cytometry, mass cytometry, and mice preclinical GBM models. Moreover, the improvement of TNFRSF14 blockade on the efficacy of PD-L1 treatment was examined in mice intracranial xenograft bearing models. TNFRSF14, a previously poorly characterized IC, was disclosed as a checkpoint with malignant intrinsic elevation closely associated with type II not type I IFN signaling activation in GBM. Anti-PD-L1 treatment induces compensatory TNFRSF14 elevation, while enhancing IFN-γ production. TNFRSF14 phosphorylates FAK at Y397 and consequently activates NF-κB, which not only strengthens the tumorigenicity of GBM cells, but also enhances TAMs recruitment through elevating CXCL1/CXCL5 secretion from GBM cells. TNFRSF14 ablation reduces the tumorigenicity of GBM cells, reshapes the immunosuppressive microenvironment, and enhances therapeutic efficacy of anti-PD-L1 in mouse orthotopic GBM model. Our findings highlight a malignant TNFRSF14/FAK axis as a potential target to blunt cancer-intrinsic resistance to ICB treatment, which may help improve the therapeutic efficiency of immunotherapy in malignancies.

Dataset Information

Immunotherapy of glioblastoma explants induces interferon-γ responses and spatial immune cell rearrangements in tumor center, but not periphery.

Publications

Immunotherapy of glioblastoma explants induces interferon-γ responses and spatial immune cell rearrangements in tumor center, but not periphery.

Similar Datasets

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