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Role of lymphatic endothelial cells in Autoimmunity and Cancer

English title Role of lymphatic endothelial cells in Autoimmunity and Cancer
Applicant Hugues Stéphanie
Number 185255
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Immunology, Immunopathology
Start/End 01.09.2019 - 31.08.2023
Approved amount 759'360.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Cellular Biology, Cytology

Keywords (8)

regulatory T cell; antigen-presentation; mouse models; cancer; autoimmunity; human samples; T lymphocyte; lymphatic endothelial cells

Lay Summary (French)

Lead
Role des cellules endothéliales lymphatiques T dans le développement de maladies autoimmunes et de cancers.
Lay summary

Notre système immunitaire possède des mécanismes permettant d’éliminer les pathogènes  tout en restant « neutre » vis à vis de nos propres tissus. Cette dernière fonction est appelée tolérance immune vis à vis du soi. Cependant, des lymphocytes T reconnaissant le soi circulent dans nos organes lymphoides secondaires, pouvant entrainer le développement de maladies autoimmunes. Des mécanismes d’inhibition des ces lymphocytes T autoréactifs existent afin de maintenir la tolérance vis à vis du soi. Lors du développement de cancers, les cellules tumorales produisent des facteurs visant à inhiber la réponse des lymphocytes T anti-tumoraux. Ceci mime un état de tolérance vis à vis des tumeurs, qu’il serait intéressant de renverser, afin de promouvoir une immunité anti-tumorale plus efficace.

Les cellules dendritiques (CD) sont spécialisées dans la présentation d’antigènes dérivés de pathogènes aux lymphocytes T afin d’initier la réponse T contre un pathogène. Elles sont également importantes dans la présentation des antigènes du soi et l’inactivation des lymphocytes T autoréactifs. Récemment, d’autres cellules résidant dans les organes lymphoides secondaires ou constituant les murs de nos vaisseaux sanguins et lymphatiques, les cellules endothéliales sanguines ou les cellules endothéliales lymphatiques, respectivement, ont également été décrites pour être impliquées pour réguler la réponse immune. Nous étudions le rôle des cellules endothéliales lymphatiques dans la régulation des lymphocytes T autoréactifs d’une part, et dans celle des lymphocytes T anti-tumoraux, d’autre part. Le but étant d’identifier des cibles spécifiques de ces cellules afin de respectivement favoriser, ou inhiber, cette fonction d’inactivation de la réponse des lymphocytes T.

Le projet relève de la recherche fondamentale, et utilise des souris génétiquement modifiées permettent d’abolir spécifiquement une fonction particulière d’un type cellulaire, et d’analyser les conséquences sur la réponse des lymphocytes T, dans des modèle murins de maladies autoimmunes et de cancers.

Direct link to Lay Summary Last update: 02.10.2019

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
202246 Harnessing dendritic cell infiltration in breast cancer for improved immunotherapy. 01.11.2021 Sinergia
166541 MHCII mediated Antigen-presentation by Lymph Node Stromal Cells in Autoimmunity and Cancer 01.09.2016 Project funding
166541 MHCII mediated Antigen-presentation by Lymph Node Stromal Cells in Autoimmunity and Cancer 01.09.2016 Project funding

Abstract

Lymph nodes (LNs) are specialized organs draining the lymph flow and orchestrating antigen (Ag) specific adaptive immunity. LN stromal cells (LNSCs) release soluble factors that facilitate the migration and interactions between hematopoietic cells, and the homeostasis of immune cells. In addition, two particular subtypes, the fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs), express Ags otherwise restricted to a small number of peripheral tissues. Direct presentation of peripheral tissue Ags (PTAs) by LECs and FRCs to self-reactive CD8+ T cells results in their abortive proliferation and deletion. Therefore, LECs and FRCs exhibit functions in LNs similar to that of medullary thymic epithelial cells (mTECs) to maintain CD8+ T cell tolerance. The current application will focus on the LEC subset.Major histocompatibility complex class II (MHCII) molecules are expressed at low levels by LECs in steady-state, and are upregulated under inflammatory conditions. Our recent studies demonstrate that the loss of MHCII expression in murine LNSCs impairs peripheral CD4+ T cell tolerance, and alters regulatory T cell (Treg) populations, resulting in signs of spontaneous autoimmunity in aged mice. The first aim of this proposal will be to determine how MHCII-restricted antigen presenting LECs impact self-reactive CD4+ T cell responses. In particular, we will assess the implication of a non-classical Ag presentation pathway, autophagy, in this process. By selectively abrogating MHCII expression and autophagy in LECs, we aim to determine the consequences on the self-reactive CD4+ T cell responses and the induction of autoimmunity.As lymphatic vessels are known to transport soluble Ags, we will test the hypothesis that LECs capture these exogenous Ags and present them to T cells. Importantly, during tumor progression, LECs substantially expand and, consequently, lymphatic drainage is increased in the tumor itself and draining LNs. Therefore, the ability of LECs to capture Ags will be potentially enhanced in a tumoral context. The second aim, an ongoing work in the laboratory, is to determine the role of Ag-presentation by LECs in tumor-associated immunity. We will dissect the molecular features of tumor-associated LECs and their ability to present tumor Ags to CD4+ T cells. The selective abrogation of their Ag presenting functions will allow us to study the impact on anti-tumor T cell immunity and, thus, tumor growth progression.Finally, studies have shown that FRCs and LECs are strongly modulated by inflammation or infections, reflecting a possible phenotypic and functional specialization of those cells depending on the organ and the immune microenvironment. As such, our third aim will be to identify key molecules that are specifically regulated by LECs in the tumor microenvironment (TME) and are implicated in the modulation of host immunity to the tumor. We hypothesise that the lymphatic endothelium in the local TME may be a strategy for targeted immunotherapy.These aims will be addressed using various gene-targeted mouse strains, in which LECs are deficient or enhanced for specific functions. These mice will be used in models of autoimmune disease and cancer. We aim to establish key collaboration with clinicians at the HUG to extend our studies to human samples from patients to assess translational aspects of our preclinical findings. Overall, our project aim to generate fundamental new insights into the contribution of LECs as unconventional Ag presenting cells (APCs) and immune modulators to peripheral T cell responses. We envisage this work will open the possibility to consider LECs as a valid therapeutic target and a novel frontier in the efforts to combat autoimmunity and cancer.
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