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Identifier 000431708
Title Study on the role of adipose tissue regulatory T cells in tumor development and response to immunotherapy
Alternative Title Μελέτη του ρόλου των ρυθμιστικών Τ κυττάτων του λιπώδους ιστού στην ανάπτυξη όγκου και την απόκριση σε ανοσοθεραπεία
Author Νεοφώτιστου-Θέμελη , Ελπίδα
Thesis advisor Βεργίνης, Παναγιώτης
Reviewer Τσατσάνης, Χρήστος
Ποντίκογλου, Χαράλαμπος
Abstract Regulatory T cells (Tregs) are pivotal in maintaining peripheral tolerance and immune homeostasis. They are recruited to the tumor microenvironment during tumor progression, facilitating its escape from immune surveillance. They abundantly express immune checkpoint molecules, namely PD-1 and CTLA-4, and are thus the main targets for immunotherapy treatments. Tregs within the visceral adipose tissue (VAT) confer protective effects against metabolic dysfunction in obesity and are reprogrammed in obesity-related inflammation. Links between obesity and cancer have already been established as metabolic dysregulation has been correlated with increased cancer incidence, aggressive tumor progression and adverse prognosis in human patients. On the other hand, improved responses to cancer immunotherapy have been reported for overweight and mildly obese individuals. To date, the mechanisms underlying this paradox remain to be elucidated. In this master thesis, we set out to explore the role of VAT Tregs in tumor progression and the development of anti-tumor immune responses, as well as in the responsiveness to immunotherapy. Our results suggest that diet-induced obesity accelerates B16.F10 melanoma progression in both male and female mice. Tumor-draining lymph nodes in obese mice display increased cellularity, though no differences are observed in the content of T cell subpopulations. The obese tumor T cell profile implies increased immune activity with reduced Treg over T effector ratios, though an overall decrease in the total number of infiltrating leukocytes correlated with the notable accelerated tumor progression. In the visceral adipose tissue there’s evidence of immune suppression, indicated by a trend for increased PD-1 levels on Tregs and CD8+ T cells alike, intensity of CTLA-4 signal on Tregs and Treg/T effector analogy, though total CD45+ infiltration was slightly increased. We also report that, although the described effects were more prominent in males than females, the trends were for the most part comparable in both genders. Identification of specific molecular signatures in VAT Tregs during tumor development and also comparisons of the transcriptome of VAT and tumor-infiltrating Tregs will shed light in the contribution of obesity and specifically on obesity-related Tregs in cancer. Overall, the inclusive approach of organismal immunometabolism acknowledges the innate implications of different systems and their combined effects on health and disease. In this light, unveiling the underlying mechanisms defining obesity and its effects on tumor responses and immunotherapy effectiveness, as well as the possible implications of VAT Tregs in this interplay would serve the dual purpose of providing immense clinical benefit but also propel our basic understanding of the intricate cross-talk between immune cell populations.
Language English
Subject Cancer
Ρυθμιστικά Τ κύτταρα
Issue date 2020-08-05
Collection   Faculty/Department--School of Medicine--Department of Medicine--Post-graduate theses
  Type of Work--Post-graduate theses
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