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The role of IL-18 and IL-1 receptor signaling in T cell development and T cell exhaustion in a murine pancreatic cancer model
Pancreatic cancer is one of the deadliest cancer types and is characterized by a highly immunosuppressive tumor microenvironment. The abundance of T cells in the tumor microenvironment has been shown to improve the prognosis for pancreatic cancer patients. Nevertheless, T cell exhaustion can cause a...
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| Format: | Dissertation |
| Sprache: | Englisch |
| Veröffentlicht: |
Philipps-Universität Marburg
2023
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| Online Zugang: | PDF-Volltext |
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| Zusammenfassung: | Pancreatic cancer is one of the deadliest cancer types and is characterized by a highly immunosuppressive tumor microenvironment. The abundance of T cells in the tumor microenvironment has been shown to improve the prognosis for pancreatic cancer patients. Nevertheless, T cell exhaustion can cause a lack T cell effector function and therefore contribute to cancer immune evasion. Cytokines, like the NLRP3-dependent cytokines IL-18 and IL-1β, are highly involved in the regulation of the function and exhaustion of T cells. Additionally, elevated levels of IL-18 and IL-1β have been found in various cancer types, inter alia pancreatic cancer. Therefore, this study aimed to characterize the role of IL-18 and IL-1β in T cell exhaustion and dysfunction in a pancreatic cancer model.
It is highly important to understand the function and plasticity of T cells in pancreatic cancer in order to find new therapy approaches. Therefore, the goal of this study was to determine i) the effect of IL-18 on T cell exhaustion in vitro, ii) the molecular mechanisms of IL-18-mediated exhaustion of CTLs, iii) the effects of IL-1β and IL-18 on Th1 and Treg differentiation in vitro, iv) the effect of IL-1R and IL-18R signaling in adoptively transferred CD4+ T cells on endogenous
T cell populations in a murine pancreatic cancer model and v) the effect of IL-1R and IL-18R signaling in adoptively transferred CD4+ T cells on tumor rejection and on the function of adoptively transferred tumor specific CTLs in a murine pancreatic cancer model.
During this study, an in vitro exhaustion model was used which showed that IL-18 induces a more severe exhausted phenotype of antigen-specific CD8+ T cells in vitro. Additionally, it was used to determine that the IL-2/STAT5/Akt/mTOR pathway plays a key role in the IL-18 mediated induction of exhaustion. Therefore, this study identified IL-18 and the IL-2/STAT5/Akt/mTOR pathway as potential targets for immunotherapy in cancer.
This study also revealed a Th1 inducing and iTreg inhibiting function of IL-18 receptor signaling in vitro and therefore provides valuable information on IL-18 receptor signaling in CD4+ T cell subsets that are important for future in vitro and in vivo studies.
IL-18R and IL-1R signaling in adoptively transferred CD4+ T cells in a murine pancreatic cancer model neither had an impact on endogenous CD4+ or CD8+ T cells nor did they influence tumor growth or tumor rejection by antigen-specific CTLs. Nevertheless, the mice strains generated during this study are a helpful tool for future studies focusing on the role of IL-18 and IL-1 receptor signaling in antigen-specific CD4+ T cells and Tregs. |
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| DOI: | 10.17192/z2023.0576 |