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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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| Contributors: | |
| Format: | Doctoral Thesis |
| Language: | English |
| Published: |
Philipps-Universität Marburg
2022
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| Subjects: | |
| Online Access: | PDF Full Text |
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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. |
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| Physical Description: | 76 Pages |
| DOI: | 10.17192/z2023.0179 |