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MHC class II-dependent T cell control of brain tumors in the meningeal niche


Michael Platten, Heidelberg University
Carsten Hopf, Mannheim University for Applied Sciences

Project description

Therapies targeting T cell driven anti-tumor immunity have shown preclinical and clinical responses in mice and patients with glioblastomas (GBM)1–3. However, GBM are characterized by a distinct immunosuppressive microenvironment that limits T cell efficacy: Tumor-infiltrating T cells show strong upregulation of immune checkpoints, reduced cytokine production, an increased exhaustion signature, and tumor infiltrating macrophages exhibit strong immunosuppressive phenotypes4,5. Interestingly, metabolic states of immune cells have recently been linked to phenotypical exhaustion and dysfunction6. Additionally, our laboratory has shown that metabolites produced by the tumor cells themselves can limit anti-tumor T cell immunity and antigen presentation7,8. From an immunological perspective, local GBM progression or relapse is the result of immune escape in distinct glioblastoma sub-microenvironments. In the lab´s unpublished work using a novel in vivo inducible microglia-specific and myeloid-specific major histocompatibility complex II (MHCII) knockout mouse model, a strong transcriptional impact on tumor-infiltrating immune cells in a syngeneic immunocompetent glioma bearing mice with a robust and strong effect on preclinical survival was found.9 Murine single immune cell sequencing-retrieved receptor-ligand analyses unexpectantly predicted unique intratumoral cytotoxic CD8-positive T cell states and cellular crosstalks dependent of myeloid-specific MHCII. Additionally, we have investigated the meninges of experimental glioblastoma-bearing mice and found spontaneous tumor-reactive T cells in the meninges suggesting the latter as relevant compartment for glioma antigen presentation. Single cell sequencing, single cell immune receptor sequencing, probe-based single cell spatial profiling, and MSI-guided laser capture microdissection liquid-chromatography mass spectrometry (LMD LC-MS) in experimental murine and human GBM meningeal niches will be performed to characterize and dissect multidirectional cellular communication. Via an integrative multiomic approach, novel targets within the meningeal niche as crystallization point for an effective control of brain tumors will be assessed.


  1. Aslan, K., et al., Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas. Nat. Commun. (2020). doi:10.1038/s41467-020-14642-0
  2. Hilf, N. et al., Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature (2019). doi:10.1038/s41586-018-0810-y
  3. Platten, M. et al., A vaccine targeting mutant IDH1 in newly diagnosed glioma. Nature (2021). doi:10.1038/s41586-021-03363-z
  4. Woroniecka, K. et al., T-Cell dysfunction in glioblastoma: Applying a new framework. Clin. Cancer Res. (2018). doi:10.1158/1078-0432.CCR-18-0047
  5. Quail, D. F. & Joyce, J. A. The Microenvironmental Landscape of Brain Tumors. Cancer Cell (2017). doi:10.1016/j.ccell.2017.02.009
  6. Franco, F. et al., Metabolic and epigenetic regulation of T-cell exhaustion. Nat. Metab. (2020). doi:10.1038/s42255-020-00280-9
  7. Friedrich, M. et al., Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas. Nat. Cancer (2021). doi:10.1038/s43018-021-00201-z
  8. Bunse, L. et al., Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat. Med. (2018). doi:10.1038/s41591-018-0095-6
  9. Kilian, M. et al., MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors. bioRxiv, (2022). doi:10.1101/2022.06.10.495502

Methods used

  • Single cell sequencing, single cell immune receptor sequencing
  • Probe-based single cell spatial profiling
  • MS imaging
  • MSI-guided laser capture microdissection liquid-chromatography mass spectrometry (LMD LC-MS)

Collaboration partners