Characterisation of immune-modulating lymphocyte populations in melanoma patients


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PhD thesis: a PhD thesis.
Characterisation of immune-modulating lymphocyte populations in melanoma patients
de Jonge Kaat
Speiser Daniel
Baumgaertner Petra
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Université de Lausanne, Faculté de biologie et médecine
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According to the World Health Organisation, cancer is the second leading cause of death in the world, causing an estimated 9.6 million deaths in 2018. In the last decades, huge strides have been made into new therapy avenues producing long lasting effects. Most of these immune-therapies focus on activating cytotoxic T cells within the tumour-microenvironment. Within the tumour-microenvironment the tumour cells as well as other types of immune cells like regulatory T cells and myeloid-derived suppressor cells can suppress the function of the anti-tumour immune response.
We hypothesized that some of the still infrequently studied lymphocytes my also hamper anti-tumour T cell responses. The aim of my thesis work was to determine whether NK cells, B cells and/or further non-T lymphocyte populations may have immunosuppressive roles, and thus could be harmful for melanoma patients.
During my first project, we studied the roles of peripheral NK cells in human late stage (III/IV) melanoma patients. We found that the abundance of CD56bright NK cells negatively correlate with overall patient survival, together with distant metastases, in a multivariate cox regression analysis. The patients’ CD56bright NK cells showed upregulation of CD11a, CD38 and CD95 as compared to healthy controls, pointing to an activated phenotype as well as a possible immune regulatory role. After stimulation in vitro, CD56bright NK cells produced less TNFα and GMCSF in patients than controls. Our results emphasizing the potential of NK cell subsets for biomarker discovery and future therapeutic targeting.
The characterisation of B cells in melanoma patients became the topic of my second project. Peripheral B cells from patients not responding to immunotherapy (Ipilimumab) produced higher levels of IL-6, TNFα and IL-10 but less GMCSF. Moreover, IL-6, TNFα and IL-10 levels also inversely correlate with overall survival. RNA sequencing from sorted B cells from within the tumour micro-environment show an enrichment in inflammatory genes, including expression of IL-6, IL-10 and LTα. One of the highest overexpressed genes is IDO. Overall, our research suggests that B cells contribute to the pro-tumoural immune response by producing both inflammatory and regulatory cytokines. B cells could thus be new targets, and/or exploited as biomarkers for therapy.
During my third project we identified a so far unknown cell population which we termed Orphan Lymphoid Cells (OLCs). They make up around 0.2% of human circulating lymphocytes. OLCs are negative for all major lineage markers but express CD44, CD45, common γ-chain (CD132) and partially CD62L. Morphological analysis and principal component analysis by RNA sequencing shows a homogeneous population. Moreover, RNA sequencing profiling shows a phenotype between T and NK cells while being distinctly different. While these data establish the existence of a new lymphocyte population in humans, more work is needed to clarify their functionality, tissue distribution and link to other immune cells.
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08/07/2019 9:42
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02/09/2019 9:00
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