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A Conceptual Framework for Inducing T Cell-Mediated Immunity Against Glioblastoma

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Abstract

Glioblastoma is a highly aggressive brain tumor with limited treatment options. Several major challenges have limited the development of novel therapeutics, including the extensive heterogeneity of tumor cell states within each glioblastoma and the ability of glioma cells to diffusely infiltrate into neighboring healthy brain tissue, including the contralateral hemisphere. A T cell-mediated immune response could deal with these challenges based on the ability of polyclonal T cell populations to recognize diverse tumor antigens and perform surveillance throughout tissues. Here we will discuss the major pathways that inhibit T cell-mediated immunity against glioblastoma, with an emphasis on receptor–ligand systems by which glioma cells and recruited myeloid cells inhibit T cell function. A related challenge is that glioblastomas tend to be poorly infiltrated by T cells, which is not only caused by inhibitory molecular pathways but also currently utilized drugs, in particular high-dose corticosteroids that kill activated, proliferating T cells. We will discuss innovative approaches to induce glioblastoma-directed T cell responses, including neoantigen-based vaccines and sophisticated CAR T cell approaches that can target heterogeneous glioblastoma cell populations. Finally, we will propose a conceptual framework for the future development of T cell-based immunotherapies for glioblastoma.

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Acknowledgements

This work was supported by a grant from NIH (P01 CA236749 to K.W.W.) and The Jennifer Oppenheimer Cancer Research Initiative at Dana-Farber Cancer Institute (to K.W.W.). S.M. is supported by a fellowship from the Deutsche Forschungsgemeinschaft (DFG, grant MA 8489/1-1).

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Author notes

  1. Sascha Marx and Anze Godicelj contributed equally.

Authors and Affiliations

  1. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA

    Sascha Marx, Anze Godicelj & Kai W. Wucherpfennig

  2. Department of Immunology, Harvard Medical School, Boston, MA, 02115, USA

    Sascha Marx & Kai W. Wucherpfennig

  3. Program in Immunology, Harvard Medical School, Boston, MA, 02115, USA

    Anze Godicelj & Kai W. Wucherpfennig

  4. Department of Neurology, Brigham and Women’s Hospital, Boston, MA, 02215, USA

    Kai W. Wucherpfennig

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  1. Sascha Marx
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  2. Anze Godicelj
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Correspondence to Kai W. Wucherpfennig.

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Conflict of interest statement

K.W.W. serves on the scientific advisory board of T-Scan Therapeutics, SQZ Biotech and Nextechinvest and receives sponsored research funding from Novartis. He is a scientific co-founder of Immunitas Therapeutics.

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This article is a contribution to the special issue on: Neuroimmune Interactions in Health and Disease - Guest Editors: David Hafler & Lauren Sansing

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Marx, S., Godicelj, A. & Wucherpfennig, K.W. A Conceptual Framework for Inducing T Cell-Mediated Immunity Against Glioblastoma. Semin Immunopathol 44, 697–707 (2022). https://doi.org/10.1007/s00281-022-00945-5

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