IL-1R8 Acts As An Immune Checkpoint In CD8+ T Cells

Supino, Domenico (2020). IL-1R8 Acts As An Immune Checkpoint In CD8+ T Cells. PhD thesis The Open University.



IL-1R8 is a member of the Interleukin-1 receptor (ILR) family, acting as a negative regulatory receptor that inhibits inflammation by dampening ILR and Toll-like receptor (TLR) signaling pathways. IL-1R8 deficiency was shown to enhance IL-18-promoted NK cell effector functions restraining tumor metastasis and viral dissemination. IL-1R8 is thus considered a new immunocheckpoint of innate lymphoid cells.

CD8+ T cells represent a potent and target-specific component of anti-tumor immunity, which can be targeted to overcome tumor-associated immune dysfunction in the context of cancer immunotherapy. The aim of this project was to dissect the role played by IL-1R8 in Cytotoxic T lymphocytes (CTLs). Expression profile analysis indicated that IL-1R8 was transcriptionally and epigenetically controlled along immune cell differentiation. In particular, IL-1R8 was upregulated as a consequence of T cell maturation in physiologic and pathologic contexts and its expression was associated with the acquisition of early-effector markers in healthy donors and tumor patients. We demonstrated that IL-1R8 genetic deficiency promoted CD8+ T cell-mediated protection in immunogenic tumor models and enhanced effector functions in IL-1R8-silenced human CD8+ T cells. Surprisingly, we found that IL-1R8 regulated T cells through the integration of two independent cell-autonomous mechanisms. IL-1R8 deficiency promoted Type-1 responses and enhanced IL-18-mediated pathway by inducing TBET. In addition, IL-1R8 regulated the IL-2/EOMES/CD25 signaling axis consequently affecting T cell maturation, proliferation and cytokines production in TBET+ EOMES+ CD8+ T cells.

The analysis of IL-1R8 transcription showed a complex mechanism of regulation, including epigenetic modifications, two transcription-starting sites and transcription of truncated isoforms.

Collectively, our data showed that IL-1R8 acts as a checkpoint for mouse and human CD8+ T cells and its expression is upregulated during the transition from naïve to mature CD8+ T cells, hence suggesting that IL-1R8 genetic targeting represents a tool to enhance the activity of CD8+ T cells, including CAR-T cells, in cancer immunotherapy.

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