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Identifier

000431732

Title

The role of inflammasome during immunotherapy responses in cancer

Alternative Title

Ο ρόλος του φλεγμονοσώματος κατά τη διάρκεια των ανοσοθεραπευτικών αποκρίσεων στον καρκίνο

Author

Παπαφράγκος, Ιωσήφ

Thesis advisor

Βεργίνης, Παναγιώτης

Reviewer

Καρδάσης, Δημήτριος
Μπερτσιάς, Γεώργιος

Abstract

Chronic inflammation is considered one of the hallmarks of cancer initiation and progression and is a critical modulator of carcinogenesis through secretion of inflammatory cytokines, which leads to the formation of an inflammatory and immunosuppressive tumor microenvironment (TME). Chronic inflammation in TME in tumorbearing patients has been accused to induce the accumulation and retention of highly immunosuppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs), through the aberrant activation of myelopoiesis resulting in their expansion and recruitment. In consistence with this, the highly inflammatory and immunosuppressive TME becomes a hotbed of immunologic activity promoting tumor growth and development, as it provides an immunosuppressive shield that protects the tumor from patient’s immune system and immunotherapy. In this process, the inflammasome plays a crucial role. The inflammasome constitutes an innate immune sensor that regulates and controls the homeostatic innate immune pathways and is a critical for the production of active IL-1β, a potent inflammatory cytokine. Although inflammasomes are essential for host defense against pathogens and contribute to autoimmune diseases, their role in tumor progression remains controversial. Inflammasomes and their effectors are able to shape the tumor milieu through their contribution to inflammation and immune responses, affecting thus the development, progression and treatment of cancer, which depicts the diverse roles of inflammasomes in modulating carcinogenesis and their potential targeting in translational research. For the present Master Thesis, we aimed to investigate how the NLRP3 inflammasome and consequently IL-1β shapes tumor growth, anti-tumor immune response and immunotherapy responses. Herein, we provide evidence for the crucial role of the NLRP3 inflammasome pathway in the establishment of melanoma. We demonstrate a pro-tumorigenic role for inflammasome’s effector IL-1β cytokine, whose presence in TME and peripheral lymphoid organs of melanoma-bearing mice is associated with tumor progression and development. Activation of the NLRP3 inflammasome pathway in myeloid cell compartment provides an inflammatory microenvironment promoting melanoma tumor progression. Finally, our data suggest that inhibition of NLRP3 inflammasome attenuates melanoma tumor growth and alters the immune cell milieu. Collectively, these findings delineate a pivotal role of NRLP3 inflammasome in carcinogenesis and offer a better mechanistic insight of how it influences tumor progression and anti-tumor immune responses, which will undoubtedly open new avenues for translational research and the development of more efficacious immunotherapeutic approaches

Language

English

Subject

NLRP3 φλεγμονόσωμα

Ιντερλευκίνη -1 Βητα (IL-1B)

Κατασταλτικά κύτταρα μυελικής σειράς (MDSCs)

Μικροπεριβάλλον όγκου

Issue date

2020-08-05

Collection

School/Department--School of Medicine--Department of Medicine--Post-graduate theses

Type of Work--Post-graduate theses