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• W2969364584 abstract "T lymphocytes are a critical component of the adaptive immune system. Efficient T cell- mediated immunity against microbial infection and cancer requires exquisitely regulated migratory patterns, which allow T cells to specifically infiltrate peripheral tissues such as skin, gut, and lung. It has been repeatedly shown that T cell infiltration of solid tumours is an important correlate of clinical outcome. Thus, a better understanding of the molecular mechanisms of tumour infiltration is essential for the development of effective cancer immunotherapy.In this thesis, we first examined the homing receptor profile of tumour-specific CD8' T cells derived from the blood of vaccinated melanoma patients. The panel of analytes comprised members of the selectin, selectin-ligand, chemokine receptor, and integrin families. We observed positive associations between clinical outcome and the expression of two analytes, P-selectin ligands, and the integrin, VLA-1. When we analysed CD8+ T cells derived from resected tumour metastases in various tissues, we consistendy observed high expression of VLA-1. Therefore, we chose to further investigate the role of VLA-1 in a mouse model of melanoma. We report that VLA-1 -expressing CD8+ T cells differentiate within subcutaneous melanoma within two weeks, and that these cells are highly activated and exhibit strong effector fonctions. Systemic treatment of tumour-bearing mice with VLA-1 fonction-blocking monoclonal antibodies led to faster tumour progression, further confirming the role of VLA-1 in tumour infiltration by T cells.The recent discovery-of tissue-resident memory T cells highhghts the need for investigation of tissue-derived, rather than blood-derived immune cells in humans. As a second project, we used the skin chamber assay, a little-used technique for the isolation of immune cells from human skin, to characterise the lymphocytic and myeloid cell infiltrate from healthy, inflamed, and microbiota-depleted skin. Our data provide interesting insight into mechanisms of T cell homing to skin under homeostatic or inflamed conditions. Moreover, we established a collaboration with Professer Gilliet (Dermatology, CHUV) in which the unique contributions of neutrophils and plasmacytoid dendritic cells to skin wound heahng were further elucidated.Altogether, this thesis demonstrates with various techniques, in both murine and human systems, the importance of tissue-resident immune cell fonction in solid tissue, with respect to tumour growth and wound heahng.--Les lymphocytes T sont des composants cles du systeme immunitaire adaptatif. Pour que la reponse immunitaire a mediation cellulaire soit efficace, il est essentiel que l'expression des marqueurs de migration, permettant aux lymphocytes T d'infiltrer specifiquement les tissus peripheriques tels que la peau, les intestins ou les poumons, soient parfaitement regules. Plusieurs etudes ont montre une etroite correlation entre la capacite des lymphocytes T a infiltrer les tumeurs solides et la survie des patients. Par consequent, une meilleure comprehension des mecanismes moleculaires impliques dans l'infiltration tumorale est essentielle au developpement d'une immunotherapie efficace contre le cancer.Nous avons ici caracterise les marqueurs de tropisme des lymphocytes T CD81 specifiquement diriges contre les tumeurs, issus de sang de patients atteints de melanome apres vaccination therapeutique. Ces marqueurs appartiennent a plusieurs familles, soitent les selectines, les ligands aux selectines, les recepteurs aux chemokines, ou les integrines. Nous avons observe que l'issue clinique correle positivement d'une part avec l'expression de l'integrine VLA-1, et d'autre part avec l'expression des ligands specifiques de la selectine P. Une forte expression de VLA-1 a ete observee a la surface des lymphocytes T CD8+ issus de metastases tumorales provenant de divers tissus. Par consequence, nous avons choisi d'approfondir l'etude du role de VLA-1 dans un modele mutin de melanome sous-cutane. Dans ce contexte, les lymphocytes T CD8+ intra- tumoraux expriment VLA-1 apres deux semaines et se caracterisent par une forte activation et capacite a secreter des cytokines inflammatoires. L'administration systemique d'anticorps monoclonaux bloquants la fonction de VLA-1 a accelere la progression tumorale dans ce modele murin. Ces resultats confirment le role de VLA-1 dans l'infiltration tumorale par les lymphocytesChez l'homme des lymphocytes T memoires residants dans les tissus ont recemment ete decouverts, soulignant la necessite d'etudier les cellules immunitaires derivees des tissus plutot que celles derivees du sang. Nous avons donc isole des cellules immunitaires de la peau humaine par le test de la chambre cutanee, une technique rarement utilisee, afin de caracteriser l'in filtrat lymphocytaire et myeloide de peau saine, enflammee ou depletee de son microbiote. Nos donnees livrent un apercu interessant des mecanismes de migration des lymphocytes T au niveau de la peau, dans des conditions homeostatiques ou d'inflammation. De plus, dans le cadre d'une collaboration nous avons eu l'opportunite d'etudier la contribution des neutrophiles et des cellules dendritiques plasmacytoides dans la guerison des plaies cutanees." @default.
• W2969364584 created "2019-08-29" @default.
• W2969364584 creator A5088763485 @default.
• W2969364584 date "2017-01-01" @default.
• W2969364584 modified "2023-09-24" @default.
• W2969364584 title "Mechanisms of Tumour Infiltration and Rétention by CD8+ T Lymphocytes in Melanoma" @default.
• W2969364584 hasPublicationYear "2017" @default.
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