Investigating the Dynamics of T cell Exhaustion in Glioblastoma and Other Solid Tumors

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Fecci, Peter

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Waibl Polania, Jessica

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2024-06-06T13:44:11Z

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2024-06-06T13:44:11Z

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2024

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Pathology

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While terminally exhausted T cells (Tex_term) retain important anti-tumor cytotoxic function, it is the relative preservation of renewable, stem-like progenitor exhaustion (Tex_prog) that better indicates immunotherapeutic responsivity. Therefore, elucidating the requirements for progression from Tex_prog to Tex_term takes on clinical significance, where the cellular interactions in a tumor microenvironment (TME) governing such progression remain poorly established. Employing glioblastoma (GBM) and other solid tumors as models of severe exhaustion, we provide a detailed characterization of the progression from Tex_prog to Tex_term within the TME, where we observe a striking and disproportionate loss of Tex_prog over time. We find exhaustion concentrated within tumor-specific T cell subsets, with cognate antigenic exposure requisite for acquisition of the Tex_term phenotype. However, we identify tumor-associated macrophages (TAM), and not tumor cells, as the source of antigenic exposure governing the Tex_prog to Tex_term transition. Using cell – cell interaction analysis, we additionally highlight candidate receptor–ligand communications that may be specifically mediating the progression to Tex_term within the TME.

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https://hdl.handle.net/10161/30806

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https://creativecommons.org/licenses/by-nc-nd/4.0/

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Immunology

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Molecular biology

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Brain metastasis

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Glioblastoma

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T cell exhaustion

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Tumor associated macrophage

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Tumor microenvironment

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Investigating the Dynamics of T cell Exhaustion in Glioblastoma and Other Solid Tumors

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Dissertation

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