Sir Peter MacCallum Department of Oncology - Theses
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ItemThe role of lysine acetyl transferases and epigenetic regulators in T-cell mediated anti-tumour immune-responses( 2023-09)Adoptive cell therapy using chimeric antigen receptor (CAR) T cells has demonstrated remarkable success in treating haematological malignancies, resulting in the FDA approval of six CAR T cell products for the treatment of B cell Acute Lymphoblastic Leukaemia, multiple myeloma and non-Hodgkin lymphoma. However, CAR T cells have shown limited efficacy against solid tumours in the clinic, which is primarily attributed to the immunosuppressive nature of the tumour microenvironment and antigen heterogeneity of solid tumours. Hence, strategies to overcome these challenges are necessary for CAR T cells to be effective in solid malignancies. Improved clinical outcomes have been associated with CAR T cells exhibiting memory T cell characteristics. While the transcriptional control of memory differentiation is extensively studied, our understanding of the epigenetic mechanisms underlying these gene expression changes have yet to be fully understood. In this thesis, primary human and mouse (CAR) T cells were utilized to study the epigenetic landscape of CD8+ T cell activation and differentiation. A485, a novel histone acetyltransferase inhibitor of P300 and CBP was discovered in a small molecule compound screen to regulate memory T cell differentiation. Treatment of T cells with A485 resulted in memory phenotype differentiation with the corresponding transcriptional changes: upregulation of T cell memory associated genes and downregulation of T cell effector associated genes. In vivo data across various mice tumour models, collectively demonstrated the potent anti-tumour effect of pre-treating (CAR) T cells with A485 prior to adoptive transfer. Given that the P300 and CBP histone acetyltransferase inhibitor A485 was found to regulate memory T cell differentiation, the role of histone acetylation in T cell activation and differentiation was investigated. Histone acetylation was found to be rapidly enhanced upon T cell activation. In addition, P300 and CBP mediated histone acetylation was found to be critical for memory T cell differentiation in the time prior to first T cell division at 24 to 48 hours post activation. H3K27ac ChIP data suggest that P300 and CBP might preferentially acetylate effector-associated super enhancers at 2 hours post T cell activation, thus leading to memory T cell differentiation upon A485 inhibition. Although, P300 and CBP are often described as an entity, this thesis, proposes potential independent roles, with CBP involved in regulating memory T cell differentiation. Overall, the results presented in this thesis improve our understanding of the role of histone acetylation in T cell activation and differentiation.