Tarnai, Rita (2024) Identification of key miRNA in T-cell exhaustion to fine-tune synthetic circuits. [Tesi di dottorato]
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| Item Type: | Tesi di dottorato |
|---|---|
| Resource language: | English |
| Title: | Identification of key miRNA in T-cell exhaustion to fine-tune synthetic circuits |
| Creators: | Creators Email Tarnai, Rita rita_t@hotmail.it |
| Date: | 13 March 2024 |
| Number of Pages: | 80 |
| Institution: | Università degli Studi di Napoli Federico II |
| Department: | Biologia |
| Dottorato: | Biologia |
| Ciclo di dottorato: | 36 |
| Coordinatore del Corso di dottorato: | nome email esposito, sergio dottorato.biologia@unina.it |
| Tutor: | nome email siciliano, velia UNSPECIFIED missero, caterina UNSPECIFIED |
| Date: | 13 March 2024 |
| Number of Pages: | 80 |
| Keywords: | t-cell, exhaustion, miRNA |
| Settori scientifico-disciplinari del MIUR: | Area 05 - Scienze biologiche > BIO/11 - Biologia molecolare |
| Date Deposited: | 15 Mar 2024 10:47 |
| Last Modified: | 29 Apr 2026 11:03 |
| URI: | http://www.fedoa.unina.it/id/eprint/15410 |
Collection description
Synthetic biology offers promising avenues for enhancing cancer immunotherapy, particularly by refining CAR-T cell strategies to combat T-cell exhaustion—a key challenge in the fight against solid tumors. In this study, we established and characterized an in vitro model of T-cell exhaustion to investigate the dynamics of chronic stimulation, particularly in the presence of immunosuppressive cytokines like TGF-β, relevant to Tumor Microenvironment (TME) conditions. Our findings correlate chronic activation with diminished cytokine production, cytotoxicity, and heightened expression of exhaustion markers—effects exacerbated by TGF-β. The study's pivot is the identification of miRNAs central to the exhaustion phenotype, utilizing miRNA sequencing followed by RT-qPCR validation. From this, we selected 15 miRNAs for the construction of responsive miRNA sensors within a novel lentiviral platform designed for assessing miRNA regulatory functions. These sensors exploit a fluorescence reduction mechanism when target miRNAs interact with synthetic mRNA containing perfectly complementary target sites. The application of this innovative miRNA sensor system elucidates the regulatory roles of specific miRNAs during T-cell exhaustion, setting the stage for the development of synthetic circuits that can modulate CAR-T cell function. The ultimate goal is to create CAR-T cells resistant to exhaustion, enhancing the efficacy of immunotherapy for solid tumors while minimizing adverse effects, including cytokine release syndrome and off-tumor cytotoxicity. This research bridges a critical gap in current cancer therapy, potentially increasing patient survival rates and the overall success of CAR-T cell treatments.
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