ArticleJournal for immunotherapy of cancer2021
Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma.
Article in Journal for immunotherapy of cancer, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers, 1 of them a synthesis that pooled it.
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Who cites it
86 citing papers in PubMed, 1 synthesis or guideline pooled it, 106 citations in OpenAlex.
- T cell immunity in glioma and potential implications for immunotherapy: A systematic review.Neuro-oncology · 2026Pooled it
- Metronomic chemotherapy plus anti-PD-1 in metastatic breast cancer: a Bayesian adaptive randomized phase 2 trial.Nature medicine · 2024Trial
- The intersection of chemokine signaling with the hallmarks of cancer in glioblastoma.Journal of neuro-oncology · 2026Review
- IL6 Supports Development of an Immunosuppressive Microenvironment and Resistance to Therapy in Glioblastoma.Cancer research · 2026Article
- Local delivery of Doxorubicin and Olaparib loaded injectable hydrogels with adjuvant radiotherapy improves survival in a glioblastoma in vivo model.Drug delivery and translational research · 2026Article
- GM-CSF downregulates type I IFN responses in glioblastoma-associated monocytes.Experimental & molecular medicine · 2026Article
- Decoding glioblastoma evolution and heterogeneity through mechanistic modeling: implications for clinical translation.Journal of experimental & clinical cancer research : CR · 2026Review
- Microglia-specificity of different markers is overridden in glioblastoma specimens.Scientific reports · 2026Article
- Co-delivering macrophage engager mRNA and PD-L1 antibody via tumor-responsive nanoparticles for glioblastoma immunotherapy.Nature communications · 2026Article
- Tumors located in the brain impair the frequency and phenotype of dendritic cells in blood and tumor.iScience · 2026Article
- Perineural invasion in digestive tract tumors: Immune system interactions and therapeutic strategies.World journal of clinical oncology · 2026Review
- Targeting metabolic-epigenetic-immune axis in cancer: molecular mechanisms and therapeutic implications.Signal transduction and targeted therapy · 2026Review
- METTL3 abrogation promotes glioma progression through regulating the ISG15-FASN axis-mediated lipid metabolism in macrophages.Nature communications · 2026Article
- Translational Models for Glioblastoma: Revolutionizing Drug Development and Personalized Medicine through Clinical Insights.Theranostics · 2026Review
- Crosstalk in the brain tumor microenvironment: mechanisms, therapeutic strategies, and clinical advances.Military Medical Research · 2026Review
- Establishment of molecular subtypes and prognostic models for glioblastoma based on non-apoptotic regulatory cell death genes.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Article
- Highly Alkaline-ResistantMicroorganisms · 2025Article
- CAF-derived LRRC15 orchestrates macrophage polarization and limits PD-1 immunotherapy efficacy in glioblastoma.Neuro-oncology · 2025Article
- Current strategies and novel immunotherapeutic approaches for overcoming immune resistance in glioblastoma.Discover oncology · 2025Review
- Dual-action nanotherapy: Temozolomide-loaded, anti-PD-L1 scFv-functionalized lipid nanocarriers for targeted glioblastoma therapy.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2025Article
26 more citing papers are in PubMed but not listed here.
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Authors and funding
24 authors at 4 institutions in 3 countries.
Funding
Abstract
backgroundGlioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought to determine to what extent this immune evasion is due to intrinsic properties of the tumor cells versus the specialized immune context of the brain, and if it can be reversed.
methodsWe used CyTOF mass cytometry to compare the tumor immune microenvironments (TIME) of human tumors that are generally ICI-refractory (GBM and sarcoma) or ICI-responsive (renal cell carcinoma), as well as mouse models of GBM that are ICI-responsive (GL261) or ICI-refractory (SB28). We further compared SB28 tumors grown intracerebrally versus subcutaneously to determine how tumor site affects TIME and responsiveness to dual CTLA-4/PD-1 blockade. Informed by these data, we explored rational immunotherapeutic combinations.
resultsICI-sensitivity in human and mouse tumors was associated with increased T cells and dendritic cells (DCs), and fewer myeloid cells, in particular PD-L1+ tumor-associated macrophages. The SB28 mouse model of GBM responded to ICI when grown subcutaneously but not intracerebrally, providing a system to explore mechanisms underlying ICI resistance in GBM. The response to ICI in the subcutaneous SB28 model required CD4 T cells and NK cells, but not CD8 T cells. Recombinant FLT3L expanded DCs, improved antigen-specific T cell priming, and prolonged survival of mice with intracerebral SB28 tumors, but at the cost of increased Tregs. Targeting PD-L1 also prolonged survival, especially when combined with stereotactic radiation.
conclusionsOur data suggest that a major obstacle for effective immunotherapy of GBM is poor antigen presentation in the brain, rather than intrinsic immunosuppressive properties of GBM tumor cells. Deep immune profiling identified DCs and PD-L1+ tumor-associated macrophages as promising targetable cell populations, which was confirmed using therapeutic interventions in vivo.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.