Targeting LAG-3+ T cells for cancer immunotherapy

Capitani, Lorenzo 2024. Targeting LAG-3+ T cells for cancer immunotherapy. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Lymphocyte activation gene 3 (LAG-3) is a promising co-inhibitory receptor target which has been shown to negatively regulate T cell responses. However, the minutiae of LAG-3 biology are poorly understood and its role as a prognostic factor in different diseases is conflicting. In this study, the role of LAG3 as a prognostic factor in colon adenocarcinoma is explored. Subsequently, in vitro cellular assays were established in order to test an array of novel small molecule inhibitors of LAG-3. In parallel the feasibility of using organoids derived from colon was explored developing a computational pipeline to aid the standardization of organoid: immune cell cocultures. Results In a publicly available dataset, LAG-3 was observed to associate with a poorer prognosis in colon adenocarcinoma, and CD8+ high T cell samples with high expression levels of LAG-3 displayed a trend towards poorer survival than CD8+ high LAG-3 low patients. Two out of the five small molecules tested were capable of preventing the inhibition of HLA-DR1 tetramer binding to Jurkat cells expressing LAG-3, however they were unable to enhance T cell activation in a short term antigen recall assay as a LAG-3 blocking antibody did. Finally, the computational pipeline established was capable of estimating that number of organoid cells in an organoid culture well within 15% of the real number of cells. Conclusions LAG-3 is a relevant prognostic marker in colon adenocarcinoma warranting further investigation. The two small molecule hits were capable of preventing the interaction of soluble HLA-DR1 with LAG-3 but this did not translate to enhanced activation in an antigen recall assay. The computational pipeline developed can aid the standardization of organoid: immune cell cocultures for future testing of LAG-3 immunotherapies and beyond.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	18 November 2024
Last Modified:	18 Nov 2024 16:22
URI:	https://orca.cardiff.ac.uk/id/eprint/174116

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