eprintid: 35920
rev_number: 20
eprint_status: archive
userid: 8712
dir: disk0/00/03/59/20
datestamp: 2025-01-17 07:01:00
lastmod: 2025-01-17 10:53:35
status_changed: 2025-01-17 07:01:00
type: doctoralThesis
metadata_visibility: show
creators_name: Agardy, Dennis Alexander
title: Immune cell dynamics in irradiated gliomas
subjects: ddc-570
subjects: ddc-610
divisions: i-140001
adv_faculty: af-14
keywords: Radiotherapy
Glioma
Immunity
abstract: Surgical resection followed by adjuvant radio-chemotherapy remains the mainstay of glioma management. However, the clinical benefit is highly limited. Therefore, there is an urgent clinical need to develop and improve novel therapeutic options. Various types of immunotherapies are emerging as promising new options for the treatment of gliomas, but their efficacy, when applied as monotherapy or in combination with standard-of-care treatment, remains low due to the highly immunosuppressive tumor microenvironment (TME) of gliomas. Thus, it is crucial to combine immunotherapies with other therapies, such as radiotherapy, that can favorably modulate the TME. However, in clinical trials, standard-of-care radiotherapy regimens have failed to show a benefit in combination with immunotherapies. To determine the optimal dosage and schedule that induces a potent immune response and modulates the TME, this study aimed to investigate the effect of different dosages and fractionations on the tumor immune microenvironment in a preclinical glioma model. In this study, I demonstrate that a single application of a medium-high dosage of 5 Gy induced the strongest T cell, NK cell, and type I IFN response, the highest expression of Cxcl10 and genes related to antigen presentation, and the lowest levels of inhibitory immune checkpoints among all tested dosages and fractionation schemes. Additionally, I identified Lgals1 expression as a marker of activated CD8+ T cells, though the functional role of Lgals1 in CD8+ T cells and its potential implications for cellular immunotherapies are currently being further investigated in ongoing research. Lastly, I identified a novel perivascular T cell niche (PVTN), in which brain-infiltrating T cells and macrophages accumulate in the brains of tumor-bearing mice and glioma patients. Preliminary data on the migration behavior of T cells suggests that these cells are detained in the niche. Understanding the cellular composition, cellular crosstalk, migration behavior, and underlying mechanisms of T cell entrapment could lead to the development of novel therapeutic strategies that release T cells from the niche, allowing them to migrate to the tumor and exert their anti-tumoral functions.
date: 2025
id_scheme: DOI
id_number: 10.11588/heidok.00035920
ppn_swb: 1915045835
own_urn: urn:nbn:de:bsz:16-heidok-359202
date_accepted: 2024-12-05
advisor: HASH(0x55b82b535b90)
language: eng
bibsort: AGARDYDENNIMMUNECELL20241205
full_text_status: public
place_of_pub: Heidelberg
citation:   Agardy, Dennis Alexander  (2025) Immune cell dynamics in irradiated gliomas.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/35920/1/DoctoralThesis_DennisAlexanderAgardy.pdf