eprintid: 32202
rev_number: 24
eprint_status: archive
userid: 6943
dir: disk0/00/03/22/02
datestamp: 2022-10-06 06:27:55
lastmod: 2022-10-10 16:11:57
status_changed: 2022-10-06 06:27:55
type: doctoralThesis
metadata_visibility: show
creators_name: Meßmer, Julia Maria
title: Dynamic intravital imaging reveals a T lymphocyte
recruitment mechanism to melanoma brain tumors
divisions: i-140001
divisions: i-50000
divisions: i-850300
adv_faculty: af-14
abstract: Cutaneous malignant melanoma is a rare, but very aggressive type of skin cancer, that frequently
metastasizes to the brain. As treatment options for patients suffering from brain metastases are very
limited, the diagnosis of brain metastasis is associated with a poor prognosis. However, recent
preclinical and clinical findings raise hope that immunotherapeutic approaches could benefit brain
metastasis patients. Intracranial anti‐tumor response to immune checkpoint inhibition (ICI) is possible
but strongly depends on efficient T cell recruitment to the brain. While the brain has long been
considered an immune privileged organ, recent studies have suggested that special meningeal
lymphatic vessels facilitate immune surveillance of brain tissue. However, in the context of brain
tumors, the mechanism of T cell recruitment to the brain, and how this is affected by ICI, is still poorly
understood. To elucidate anatomical and molecular mechanisms of T cell homing to brain tumors, I
established novel intravital microscopy methods that allow to track T cell and tumor cell interactions
in real‐time over two weeks in two different syngeneic mouse models for melanoma brain tumors.
With this, I was able to visualize the dynamics of T cell recruitment to the brain during tumor
development, and I discovered a new route for circulating T cells to access brain tumors via distinct
anatomical structures, namely peritumoral venous vessels (PVVs). Exploitation of PVVs for T cell
homing to intracranial tumors was enhanced by ICI treatment. I could demonstrate that PVVs are the
sites where circulating T cells preferably arrest and extravasate. Other structures, such as brain
capillaries, intratumoral blood vessels, and parasagittal regions could be excluded as alternative T cell
routes to intracranial melanoma. Moreover, at PVVs, a particularly high T cell motility and number was
observed, and PPVs were characterized by high luminal expression of the endothelial intercellular
adhesion molecule 1 (ICAM‐1). Indeed, a trend of mitigation of ICI‐mediated T cell infiltration and
intracranial tumor growth control could be detected following functional blocking of ICAM‐1 in vivo.
ICI treatment increased T cell motility in the brain, facilitating the route from the PVV to the tumor,
which resulted in intracranial tumor growth inhibition. These findings describe a distinct mechanism
by which cellular components of the adaptive immune system can access and control brain tumors,
and potentially other brain pathologies. The molecular and cellular features of PVVs, and also the
specific effects of ICIs on T cell functionality in the brain in vivo, which is described for the first time,
provide a fundament which will help to further improve immunotherapies against brain tumors.
date: 2022
id_scheme: DOI
id_number: 10.11588/heidok.00032202
ppn_swb: 1818397358
own_urn: urn:nbn:de:bsz:16-heidok-322025
date_accepted: 2022-09-19
advisor: HASH(0x5644fa3efc30)
language: eng
bibsort: MESSMERJULDYNAMICINT20220927
full_text_status: public
place_of_pub: Heidelberg
citation:   Meßmer, Julia Maria  (2022) Dynamic intravital imaging reveals a T lymphocyte recruitment mechanism to melanoma brain tumors.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/32202/1/PhDThesis_JuliaMessmer.pdf