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Isolation and Flow Cytometric Analysis of Glioma-infiltrating Peripheral Blood Mononuclear Cells
Published on: November 28, 2015
Inhibiting interferon-γ induced cancer intrinsic TNFRSF14 elevation restrains the malignant progression of
Yunhe Han1, Cunyi Zou1,2, Tianqi Liu1
1Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, China.
Background:
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).
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
This study reveals that TNFRSF14 is a key immune checkpoint driving glioblastoma resistance to immunotherapy. Blocking TNFRSF14 may enhance treatment efficacy for glioblastoma (GBM) and other cancers.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Prolonged interferon-gamma (IFN-γ) signaling promotes cancer resistance to therapies, including immunotherapy.
- Mechanisms of this resistance, particularly in glioblastoma (GBM), are not fully understood.
- Identifying key immune checkpoints involved in GBM's immunosuppressive microenvironment is crucial.
Purpose of the Study:
- To explore intrinsic cancer resistance mechanisms against immune checkpoint blockade (ICB).
- To identify immune checkpoints contributing to GBM's suppressive immune microenvironment.
- To investigate the role of TNFRSF14 in IFN-γ-mediated resistance and its therapeutic potential.
Main Methods:
- Integrated transcriptomic profiling to screen immune checkpoints (ICs) associated with IFN signaling in GBM.
- Functional assays (in vitro and in vivo) to evaluate TNFRSF14 expression, proliferation, and tumorigenicity.
- Preclinical GBM models to assess the therapeutic efficacy of TNFRSF14 disruption and combination with anti-PD-L1 therapy.
Main Results:
- TNFRSF14, a poorly characterized IC, is upregulated by IFN-γ signaling in GBM, enhancing proliferation and tumorigenicity.
- Anti-PD-L1 treatment can induce compensatory TNFRSF14 elevation, increasing IFN-γ production.
- TNFRSF14 activation of the FAK/NF-κB axis promotes GBM cell tumorigenicity and TAMs recruitment via CXCL1/CXCL5.
- TNFRSF14 blockade reduces GBM tumorigenicity, reshapes the immune microenvironment, and enhances anti-PD-L1 efficacy.
Conclusions:
- The TNFRSF14/FAK axis represents a novel mechanism of cancer-intrinsic resistance to ICB.
- Targeting TNFRSF14 offers a potential strategy to overcome resistance to immunotherapy in GBM.
- This finding may improve the therapeutic efficiency of immunotherapy in various malignancies.
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