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
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