The manifold roles of immunoproteasome and short-chain fatty acids in shaping the anti-tumor immune responses

The mucosal immune system is shaped by tight interactions between immune cells and host microbiota. However, the factors contributing to the development of a functional immune system with a finely regulated homeostasis remain poorly understood. Here, we demonstrated the impact of the microbial m...

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Bibliographic Details
Main Author: Leister, Hanna Katharina
Contributors: Visekruna, Alexander (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Language:English
Published: Philipps-Universität Marburg 2022
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Summary:The mucosal immune system is shaped by tight interactions between immune cells and host microbiota. However, the factors contributing to the development of a functional immune system with a finely regulated homeostasis remain poorly understood. Here, we demonstrated the impact of the microbial metabolites SCFAs on the effector function of immune cells by modulation of metabolic state, as well as epigenetic regulation via HDAC inhibition. Especially the physiologically abundant SCFAs butyrate and pentanoate elicited beneficial effects on the effector function of CD8+ T cells and might be considered for anti-cancer therapy implementation. In the second part of this study, we discovered that the proteasome, as a main checkpoint in cellular function, displays opposing roles in tumor development. As an activator of NF-κB, the immunoproteasome impacts on the expression of pro-inflammatory mediators. Consequently, the immunoproteasome exhibits pro-tumorigenic capacity in an inflammatory-driven carcinogenesis, such as colitis-associated cancer, by enhancing the expression of cytokines and chemokines, contributing to immune cell infiltration and inflammation. On the other side, the immunoproteasome might generate neo-antigens for presentation via MHC class I molecules, thereby enabling cytotoxic T cell response against solid tumors. We demonstrated that the lack of immunoproteasome subunits (LMP7, LMP2 and MECL-1) protects mice against the development of colitis-associated carcinogenesis, but in melanoma microenvironement, high expression of immunoproteasome is required to induce an efficient anti-tumor response.
Physical Description:76 Pages
DOI:10.17192/z2023.0179