Investigation of the role of cancer associated fibroblasts in the generation of tumor-specific T regulatory (Treg) cells that promote tumor development

Postgraduate Thesis uoadl:2879204 77 Read counter

Unit:
Κατεύθυνση Μοριακή Βιοϊατρική - Μηχανισμοί Ασθενειών, Μοριακές και Κυτταρικές θεραπείες και Βιοκαινοτομία
Library of the School of Health Sciences
Deposit date:
2019-07-18
Year:
2019
Author:
Varveri Athina
Supervisors info:
Παναγιώτης Βεργίνης, Ερευνητής Γ', Ίδρυμα Ιατροβιολογικών Ερευνών Ακαδημίας Αθηνών
Δημήτριος Μπούμπας, Καθηγητής, Ιατρική, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Αριστείδης Ηλιόπουλος, Καθηγητής, Ιατρική, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Original Title:
Investigation of the role of cancer associated fibroblasts in the generation of tumor-specific T regulatory (Treg) cells that promote tumor development
Languages:
English
Translated title:
Investigation of the role of cancer associated fibroblasts in the generation of tumor-specific T regulatory (Treg) cells that promote tumor development
Summary:
T regulatory cells (Tregs), as the most abundant immune suppressive cells of the TME, have been associated with impeding potent anti-tumor immune responses and impairing the success of immunotherapies. To this end, inhibiting or eliminating them is considered an attractive option for cancer treatments, as targeting them may facilitate containment of the growing tumor. However, in order to eliminate only tumor-infiltrating Tregs without affecting the peripheral Tregs, it is an urgent need to find out the mechanisms and molecules responsible for their recruitment and expansion in the TME. A dominant component of the TME, whose role as potential regulators of the anti-tumor immunity has only recently started to be explored, is Cancer Associated Fibroblasts (CAFs). Mainly through their secretome, CAFs are capable of affecting the induction and accumulation of Tregs in the TME. However, the mechanisms behind CAF-mediated immune suppression remain elusive until today.
For the present Master Thesis, we aimed to directly assess the potential cross-talk between CAFs and cells of the anti-tumor immunity, with focus on Tregs. Herein, we demonstrate a significant enrichment of α-SMA+ CAFs in the TME of mouse melanoma, while a clear α-SMA+ population was detected in circulation in later tumor stages. Specific ablation of α-SMA+ CAFs before melanoma induction resulted in significant regression of tumor growth, accompanied with elevated numbers of tumor infiltrating CD45+ cells and increased numbers of intratumoral Tregs. Furthermore, following CD4+FoxP3- naive T cells culture in Treg induction conditions with TES vs TESCAFsΔ, we found Foxp3 expression levels to be significantly downregulated in the presence of TESCAFsΔ, while their proliferation was hindered as well.
Collectively, our data bring into focus CAFs as an important cell population with immune-suppressive properties, characterized by a potency to induce highly immunosuppressive populations, such as Tregs. Elucidation of how this role of theirs unfolds shall provide a better mechanistic insight of how CAFs hinder tumor immune responses and ultimately lead to development of more efficacious immunotherapeutic approaches.
Main subject category:
Health Sciences
Keywords:
Cancer, Melanoma, Cancer associated fibroblasts, Regulatory T cells, Immunotherapy
Index:
No
Number of index pages:
0
Contains images:
Yes
Number of references:
139
Number of pages:
63

AVarveri MSc Thesis.pdf
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