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Oral Sessions
Day 2, June 23（Mon.） 14:55-15:10
Room C (Top of Yaima)
- 2C-O2-1455
Specific Enhancement of Neoantigen Presentation by Targeted Proteasomal Degradation
(1SIgN, A*STAR, 2NUS)
oIlisia Ow1,2, Amanda Lee1, Justin Low1, Wei Wu1,2
Neoantigen-based cancer immunotherapies hold great promise, yet their success is often hindered by inefficient neoantigen presentation. Cancer neoantigens must compete with an overwhelming abundance of self-peptides, ultimately leading to poor neoantigen visibility. Current strategies like IFN-γ treatments attempt to enhance antigen presentation collectively but fail to specifically boost neopeptide presentation. Consequently, lowly abundant neoantigens remain overshadowed. While extensive efforts have been dedicated to identifying neoantigens, these efforts are futile if poor neoantigen presentation remains a fundamental barrier. The proteasome plays a central role in antigen processing, however its lack of specificity for mutant proteins results in indiscriminate degradation and self-peptide saturation. We propose a novel strategy to enrich the immunopeptidome with neoantigens by biasing proteasomal degradation towards cancer-specific proteins. Using targeted protein degraders, we mechanistically investigated this approach by directing proteasomal activity against tumour-associated STAT3 protein. Through mass spectrometry analysis, we proved that selective STAT3 degradation reshapes antigen presentation landscape, shifting the immunopeptidome towards neoantigen visibility. These initial findings suggest a viable method to overcome the bottleneck of neoantigen presentation, for improving cancer immunotherapy efficacy. Our future work will focus on uncovering whether this increase in neoantigen visibility heightens T-cell responses.