Fernandez Patel, Shanila; (2025) Inhibition of the nonsense-mediated mRNA decay pathway for neoantigen generation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Tumour-specific neoantigens are essential for sustaining anti-tumour immune responses. Frameshift insertions/deletions (fs-indels) represent a class of mutations that can generate non-self-peptides with high immunogenic potential. However, fs-indels frequently lead to premature termination codons (PTCs), which are targeted for degradation by the nonsense mediated mRNA decay (NMD) pathway. Notably, some PTC-containing transcripts evade NMD degradation, resulting in the production of highly immunogenic neoantigens. This thesis explores whether NMD inhibition can prevent the degradation of fs-transcripts and thereby enhance neoantigen generation. By leveraging large clinical cohorts of patient data with immune-oncology response, SMG1 was identified as the optimal target within the NMD pathway for effective NMD inhibition. Modulation of SMG1 upregulated the expression of NMD-targeted PTC-containing transcripts across multiple cancer cell lines. Next, I examined whether stabilised PTC-containing transcripts following SMG1 inhibition were subsequently translated into protein. Given the clinical relevance of p53 as a frequently altered gene in cancer with high immunogenic potential, I focused on how NMD inhibition specifically affects p53 fs-transcripts. To this end, I developed a live cell imaging assay that allows to assess the translational state of individual NMD-targeted p53 fs-transcripts. This assay revealed that 40-90% of the upregulated p53 fs-transcripts were actively translated. Finally, I investigated whether the proteins derived from these preserved PTC-containing transcripts upon SMG1 inhibition led to neoantigen generation on tumour cells. Immunopeptidomics analysis demonstrated an increase in the number of unique peptides presented on the surface of tumour cells after SMG1 inhibition, a subset of which originated from NMD-targets. In conclusion, this thesis provides a comprehensive analysis of the molecular steps involved in neoantigen generation following NMD inhibition, from transcript stabilisation to human leukocyte antigen (HLA)-mediated presentation of novel antigenic peptides on tumour cell surfaces. These findings highlight the potential of NMD inhibition as a strategy to enhance cancer immunotherapy.

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